=Paper=
{{Paper
|id=Vol-2807/paperK
|storemode=property
|title=Foundations for a Realism-Based Ontology of Protein Aggregates
|pdfUrl=https://ceur-ws.org/Vol-2807/paperK.pdf
|volume=Vol-2807
|authors=Lauren Wishnie,Alexander P. Cox,Alexander D. Diehl,Werner Ceusters
|dblpUrl=https://dblp.org/rec/conf/icbo/WishnieCDC20
}}
==Foundations for a Realism-Based Ontology of Protein Aggregates==
https://ceur-ws.org/Vol-2807/paperK.pdf
Foundations for a Realism-Based Ontology
of Protein Aggregates
Lauren WISHNIE1, Alexander P. COX, Alexander D. DIEHL, Werner CEUSTERS
Department of Biomedical Informatics, University at Buffalo, USA
Abstract. The objective of this paper is to propose formal definitions for the terms
‘protein aggregate’ and ‘protein-containing complex’ such that the descriptions and
usages of these terms in biomedical literature are unified and that those portions of
reality are correctly represented. To this end, we surveyed the literature to assess the
need for a distinction between these entities, then compared the features of usages
and definitions found in the literature to the definitions for those terms found in
Bioportal ontologies. Based on the results of this comparison, we propose updated
definitions for the terms ‘protein aggregate’ and ‘protein-containing complex’. Thus
far, we propose the following distinguishing factors: first, that one important
difference lies in whether an entity is disposed to change type in response to certain
structural alterations, such as dissociation of a continuant part, and second that an
important difference lies in the ability of the entity to realize its function after such
an event occurs. These distinctions are reflected in the proposed definitions.
Keywords. Protein aggregates, protein complexes, realism-based ontology
1. Introduction
Researchers in biomedical ontology have thus far not addressed carefully enough how
biological entities known as ‘protein aggregates’ should be represented faithfully to
reality. They are not represented at all in any large biomedical ontology, and the two
smaller ontologies in which they are represented provide incomplete definitions which
lack unity and do not include all defining characteristics which differentiate them from
protein complexes [1,2]. Other ontologies refer to these entities only indirectly through
definitions for other terms such as ‘protein aggregation’. This is consistent with the fact
that definitions as provided in the biomedical literature are scarce and lack unity. These
definitions also do not accurately represent the scope of protein aggregate types that exist.
Protein aggregates (PAs) are participants in several clinically relevant pathological
bodily processes, most notably neurodegeneration [3–5] and biological processes like
cell migration [6].
In light of this, the existing definitions should be updated in such a way that the
portion of reality, in this case protein aggregates, is accurately represented. The goal of
the work presented here is to unify the descriptions and usages of multiple specific
objective truths concerning PAs in a way that allows deduction of objective truth from
the references. To accomplish this, we created a minimal set of terms, along with
ontological definitions for those terms, which will serve to describe the unified objective
1
Corresponding author, Department of Biomedical Informatics, Jacobs School of Medicine and Biomedical
Sciences, University at Buffalo, 77 Goodell street, 5 th floor, Buffalo NY 14203, USA. Email:
lmwishni@buffalo.edu.
Copyright © 2020 for this paper by its authors. Use permitted under Creative Commons License Attribution 4.0 International (CC BY 4.0).
truth concerning the characteristics of PAs. The terms that are contained in this set can
then be used as contextual templates for discerning specific instances of these terms in
the literature. The ontology which will be constructed based upon these new definitions
will be specific to the domain of the biomedical sciences—the realm of PRO and GO.
2. Background
The term ‘protein aggregate’ is used loosely, and is employed as an informal term for
entities which have as continuant parts proteins which are not in their ‘native state.’ As
such, the use of ‘protein aggregate’ is in some cases a stylistic choice, rather than a
semantically intentional choice. For clarity, this term should be reformulated.
2.1. Protein Aggregates in Neurodegenerative Disease
Protein aggregates are referenced in terms of their role in neurodegenerative diseases in
a substantial portion of biomedical literature. For example, the presence of PAs, along
with the death of specific types of neurons, are diagnostic criteria in Parkinson’s disease
(PD) patients [7]. In fact, the bodily process of protein aggregation in PD may be
influenced by impairments in the ability of neurons to degrade damaged, mutated, or
misfolded instances of the protein α-synuclein, which form unstructured clumps,
instances of which are commonly referred to as protein aggregates [8].
2.2. Protein Aggregates in Non-Neurodegenerative Disease Contexts
The antibody—antigen complexes which form as part of the immune response process
are also better understood as a type of PA. In these complexes, antibodies aggregate
around and facilitate destruction of antigens. The term ‘immune complex’ is widely used,
but we argue that the characteristics of immune complexes do not meet the criteria of yet
other entities which are currently called ‘protein complexes’ or ‘protein-containing
complexes’. Through the process of ‘immune complex formation’, specific subtypes of
antibodies cause agglutination of particulate antigens or precipitation of soluble antigens
[9]. In particular, multivalent antigens induce a process of cross-linking of antigen
particles with antibodies as the links, resulting in a ‘clump’ of antigen particles
interspersed with antibodies [9]. This clump of antibodies and antigens is referred to as
the ‘antibody—antigen complex’, although not all antigens an antibody may act upon
are necessarily macromolecules, and not all constituent parts necessarily function
together.
2.3. Protein Aggregates in Non-Disease Contexts
‘Protein aggregate’ as a category also includes entity types of which not all instances are
participants in disease processes, but rather are participants in normal physiological
processes. One example is the cytoskeletal actin filaments which form aggregates as part
of the processes of cell growth, division, and motility. Actin filaments form a network
wherein they polymerize and depolymerize to form a pseudopod so the cell can migrate,
or of membrane protrusions called ‘microvilli’ which facilitate nutrient absorption [10].
During polymerization, individual actin proteins self-assemble around an actin trimer,
elongating and shrinking the filament via addition or loss of actin subunits on either end
[11]. The rates of association and dissociation of actin subunits depends upon which
nucleotide is bound to the subunit in question [6]. This allows for the relatively tight
control of filament length. While the nucleation step of actin polymerization does require
an actin trimer, the size of individual actin filaments themselves vary between instances,
depending on what specific process is taking place.
3. Methods
We first reviewed the literature to assess the need for a distinct term for entities which
form via physical associations of proteins and other molecules, but which did not suit the
criteria for ‘protein-containing complex’. A search of the MeSH headings in PubMed
was performed to assess the numbers of papers concerning protein aggregates and protein
complexes found in all MeSH categories (Table 1). Each MeSH heading was added to
the search, followed by either “protein aggregate*” or “protein complex*”. We then
assessed the existing definitions of ‘protein aggregate’ in the literature (Table 2). For this
assessment, we performed a PubMed search for the phrase “protein aggregate”, using the
filters: ‘free full text’, ‘books and documents, ‘reviews’, ‘systematic reviews’. These
filters were selected on the basis that these particular source types, because they are
syntheses of information, are more likely to contain an explicit definition for a term than,
for example, a clinical trial. These publications were assessed to determine if they
contained a definition for ‘protein aggregate.’ This process was repeated for the search
term ‘protein complex’ with the same filters.
From this literature search, we collected examples of contextual usages and
definitions of the terms ‘protein aggregate’ and ‘protein complex’ and identified key
features contained within them, which were then compared with the contents of current
ontological definitions (Table 4). Using the information obtained from these literature
assessments, we propose definitions for the term ‘protein aggregate’, as well as changes
to the definition of ‘protein-containing complex’, both based following the principles
underlying the Basic Formal Ontology [12].
4. Results
Table 1 shows the prevalence of the phrases ‘protein aggregate’ and ‘protein complex’
in the literature. The search term ‘protein aggregate’ yields barely 70 percent of the
number of results for the search term ‘protein complex(es)’. Interestingly, ‘protein
aggregate’ appears most frequently in the biomedical literature under MeSH subheadings
‘Nervous System Diseases’’, while ‘protein complex’ appears most frequently under
‘Neoplasms’. Both terms are abundant under the subheading ‘Pathological Conditions,
Signs and Symptoms’.
Table 2 lists the definitions for the terms ‘protein aggregate’, ‘protein complex’, and
‘protein-containing complex’ as found in the literature. ‘Protein aggregate’ seems to be
used when referring to an entity which is composed of component proteins as its
continuant parts, which are noncanonical (e.g., misfolded) in some way. Protein
complexes seem to be understood as consisting only of molecules in their native states
as constituent parts. Those constituent parts function together and thus allow the complex
to bear a specific role in a specific biochemical process.
Table 1. Results of search for the term ‘protein aggregate’ under the listed MeSH subheadings.
MeSH Disease Subheading ‘protein aggregate*’ ‘protein complex*’
Disorders of Environmental Origin 0 0
Occupational Diseases 0 17
Otorhinolaryngologic Diseases 3 75
Stomatognathic Diseases 8 64
Wounds and Injuries 23 79
Skin and Connective Tissue Diseases 35 679
Chemically-Induced Disorders 39 72
Respiratory Tract Diseases 41 277
Hemic and Lymphatic Diseases 42 486
Male Urogenital Diseases 43 371
Female Urogenital Diseases and Pregnancy
49 391
Complications
Immune System Diseases 70 650
Digestive System Diseases 86 597
Endocrine System Diseases 88 305
Eye Diseases 152 250
Musculoskeletal Diseases 158 412
Cardiovascular Diseases 176 303
Infections 204 850
Neoplasms 252 2352
Congenital, Hereditary, and Neonatal Diseases and
404 967
Abnormalities
Animal Diseases 425 433
Nutritional and Metabolic Diseases 591 711
Pathological Conditions, Signs and Symptoms 1191 1902
Nervous System Diseases 2242 1198
The definitions of the terms in question are informed by their usage, and vice versa.
Thus it is important to assess the ways in which the terms are used in the literature even
when a definition is not provided. Examining common uses of prospective ontology
terms allows us to differentiate between a term’s formal definition and the ways in which
it is used practically. ‘Protein aggregate’ seems typically used when referring to entities
which participate in a disease process of some type and which do not appear to participate
in normal biological processes. ‘Protein complex’ is indeed used when referring to
entities which are participants in a specific biological process (Table 3).
Table 2. Definitions for ‘protein aggregate’ and ‘protein-containing complex’ in the literature.
Protein “Protein aggregates are oligomeric complexes of non-native conformers that arise from
aggregate non-native interactions among structured, kinetically trapped intermediates in protein
folding or assembly.”[13]
“[…] Protein aggregates be defined as any protein species in non-native states and
whose sizes are at least twice as that of the native protein. Dimers, trimers, which
maintain the native-like state will not fall under the definition of aggregates.”[14]
Protein “Protein complexes are molecular machines that perform many of the key biochemical
complex activities essential to the cell e.g. replication, transcription, translation, cell signalling,
cell-cycle regulation and oxidative phosphorylation.” [15]
“[…] a collection of proteins that copurify together in a high-throughput proteomics
experiment or through the analysis of patterns within pairwise interaction data.” [16]
Protein- “A stable assembly of two or more macromolecules, i.e. proteins, nucleic acids,
containing carbohydrates or lipids, in which at least one component is a protein and the constituent
complex parts function together.” [17,18]
Table 3. Examples of ways in which the terms ‘protein aggregate’, ‘protein complex’, ‘protein-
containing complex’, and ‘macromolecular complex’ are used in the literature.
Term Usage examples
Protein “[…] highly-ordered, β-sheet rich, insoluble aggregates are implicated in a diverse
aggregate group of neurodegenerative diseases, including prion, Alzheimer, Parkinson and
Huntington disease. In aged patients, often different aggregated proteins coexist.”
[19]
“Ordered aggregates are nm-long (un)branched amyloid fibrils, arranged in a cross
β-sheet structure [3]. Disordered aggregates […] are the result of acute cellular
stimuli (i.e., stress-caused denaturation, lack of assembly partners).” [20]
Protein “Independent evidence from global quantification of both protein production and
complex decay using ribosome profiling and metabolic pulse labeling experiments has
culminated in a conserved principle that the proportion of complex components is
indeed carefully maintained.” [21]
The definitions from the NIF Standard Ontology, the Neurodegenerative Disease
Data Ontology, the EDAM Ontology, and the Semantic Science Integrated Ontology
overall tend to track with common usages and informal definitions in the literature.
Across these representations, the term ‘protein aggregate’ refers to an entity which has
as constituent parts non-native proteins (Table 4).
Table 4 reflects the heterogeneity of the terms ‘protein aggregate’ and ‘protein
complex’ amongst the ontologies in which they are represented. The class hierarchies for
the two Bioportal ontologies containing the term ‘protein aggregate’ are distinct from
one another, save that the hierarchies are claimed to be rooted in the Basic Formal
Ontology. The hierarchies for those ontologies in Bioportal which contain the term
‘protein complex’ are also distinct The Semantic Science Integrated Ontology is inspired
by the BFO and classifies ‘protein complex’ as an object, while the ‘logic’ of the EDAM
Ontology hierarchy represents protein complexes as structures which are of type ‘data’.
Table 4 shows features from the literature definitions and usages to show common
themes, as well as gaps between these and what is represented in the listed ontologies.
These features were added to a column if they appeared in that definition. It is clear from
examining these features that across usage and definition, protein complexes are
understood to at the very least have native-state proteins as their constituent parts. Usages
and definitions in the literature indicate an understanding that within protein complexes,
continuant parts of different types appear in consistent proportion to one another between
instances in protein complexes and that those constituent parts function together, but the
SIO definition does not reflect this (Table 2, Table 3). Assessment of usages and
definitions for ‘protein aggregate’ indicate that they are widely understood as rigid and
insoluble, having as constituent parts proteins which are not in their native state. Specific
structural features like β-sheets appear frequently in usages, but do not appear in
definitions.
Table 4. Representational characteristics of ‘protein aggregate’ and ‘protein complex’ in Bioportal
ontologies .
Semantic
Neurodegenerative
NIF Standard Science
Disease Data EDAM Ontology
Ontology Integrated
Ontology
Ontology
Term protein protein aggregate protein complex protein complex
aggregate
Definitions A grouping of An insoluble mass of 3D coordinate and A protein
misfolded misfolded proteins associated data for a complex is a
proteins that is [2] multi-protein molecular
often rigid and complex; two or more complex
insoluble polypeptides chains composed of at
[1] in a stable, functional least two
association with one polypeptide
another [22] chains.
Features of Component Insoluble Constituent parts of Comprised of
Usage proteins in non- Component proteins the protein complex two or more
Examples & native state in non-native state function together polypeptides
Literature Comprised of two or
Definitions more polypeptides
1st Parent Aggregate Material entity Protein structure Molecular
object complex
2nd Parent Object Independent Structure Chemical entity
aggregate continuant
3rd Parent Material entity Continuant Data Material entity
th
4 Parent Independent Entity Thing Object
continuant
5th Parent Continuant Entity
th
6 Parent Entity
Based on these results we argue that PAs meet the definition of ‘object’ according
to the BFO [12]. An object is a maximal causally unified material entity. PAs are causally
unified via internal physical forces: if a continuant part c of a protein aggregate p1 at t1
(i.e. a portion of the aggregate on its interior) is moved in space at t2 to be at a location
on the exterior of the spatial region that was previously occupied by p1 at t1, then p1 is
either damaged or its other parts are also moved [12]. The important part to notice here
is that to meet the criteria for an object, c must move in space to a location already
occupied by p1, not in a different direction from the central axis of p1 itself. Put another
way, an instance of a PA of some type can be understood as a bound system which
requires an intervention of a sufficient magnitude to overcome the bonds between its
constituent parts and result in damage to the aggregate [23]. Bearing this in mind, the
proposed definition – using the GO-term ‘cellular component’ which despite what the
name might suggest does include entities which exist outside the cell such as the
extracellular matrix – is as follows:
Protein aggregate= def. an BFO:Object of a type instances and some parts of
these instances are, or once were, cellular components and have as primary
constituents at least two instances of PROTEIN which comprise the majority
of instances of macromolecules contained within the aggregate.
Axiom 1: An instance pa1 of PROTEIN AGGREGATE at t1 remains an instance
of PROTEIN AGGREGATE at t2 when a continuant part is added or removed
as long as there are at least two instances of PROTEIN in pa1 at t2 and as long
as the part added is of the same type as any of the continuant parts of pa1 prior
to the change.
Axiom 2: As long as an instance pa1 of PROTEIN AGGREGATE remains an
instance of PROTEIN AGGREGATE, it remains an instance of the same
subtype of protein aggregate as long as any part added is of the same type as
any of the continuant parts of pa1 prior to the change
We also propose to change the GO definition of ‘protein-containing complex’ as
PCCs have causal unity for the same reasons as protein aggregates do [12]. The proposed
definition is as follows:
Protein-containing complex= def. an BFO:Object which is a cellular component,
of a type instances of which have two or more macromolecules, i.e. proteins,
nucleic acids, carbohydrates or lipids, in which at least one component is a
protein and the constituent parts are disposed to function together only when all
constituent parts are present within the complex.
Elucidation 1: An instance of a particular protein-containing complex at t1 becomes
of a different type of BFO:Object at t2 when a continuant part is removed.
5. Discussion
An assessment of the available literature concerning PAs, compared with literature
concerning protein complexes, yields some interesting observations. The first is that
protein complexes are likely a more widespread topic of research and review than are
protein aggregates. It also seems that the term ‘protein complex’ is used outside of the
scope of its definition, and that sometimes, the more appropriate term to use is ‘protein
aggregate’. Additionally, when PAs are discussed in the literature, it is most often in the
context of neurodegenerative disease and general pathological conditions. The examples
of usages and definitions further point to a specific discrepancy in how these terms are
used: ‘protein aggregate’ is used more commonly in a disease-specific context, while
‘protein complex’ is used with greater versatility and more frequently under a broader
range of MeSH subheadings.
Protein-containing complexes are fundamental participants in bodily processes.
Among types of PCCs, there is diversity and specificity in the disposition of the
individual proteins to form a stable, correctly-folded secondary and tertiary structure [25].
It appears that some PCCs are comprised, at least in part, of constituent parts which are
proteins that are disposed to do this, while others have as constituent parts individual
proteins which do not. Specific instances of proteins within these PCCs may serve as
stabilizers of the other proteins within the complex, while other types of PCCs do not
need these support proteins [26].
An important distinction between aggregates and complexes is that an instance of a
particular aggregate can have a component protein dissociate or detach with no change
in type at that level. This is because PAs as types are not restricted to a specific number
of individual continuant parts in the same way PCCs are. This matters in the context of
the size of a specific instance of the entity, as PAs have fewer constraints on maximum
area and mass than do PCCs and thus possess fewer spatial restrictions. Another key
distinction lies in the degree of regularity or order in the arrangement of the components.
PCCs form ‘molecular machinery’ networks, which must be precisely structured and
contain all instances of their components in order to perform their function correctly [27].
Conversely, PAs vary structurally from instance to instance, and are less restricted in
terms of size and shape than PCCs, as seen in the antibody—antigen example. Our
understanding of PCCs and PAs is consistent with Schulz and Jansen’s work on grains,
components, and mixtures [28]. In this view, PCCs meet the definition of strict
compounds—for example, all components of a PCC need not be of the same type but
their number is critical. PAs can be understood as a type of flexible compound in that
they possess as continuant parts instances of collectives of individual proteins.
Importantly, collectives as a type are flexible with regard to their number of grains, which
is consistent with our understanding of PAs. From this knowledge, it can be extrapolated
that components of a PA are capable of higher degrees of disorder than the components
of a PCC.
Alterations in the ability of a protein complex to realize its function can be achieved
through a few avenues. First, the cause of the change must be determined. It is well
established that proteins can dissociate from one another and lose their tertiary and
quaternary structures, thus losing the ability to perform their function, for example as a
result of the pH of the environment differing from their pKa [29]. Thus it is often not a
question of whether the change is functional or environmental, but which came first.
The relationship between components and realization of function seems to serve as
a dividing line between PAs and PCCs. For example, an instance of PA which is
comprised of 600 individual protein molecules will not cease to be a PA of that type if
1/3 of those protein molecules are removed. Further, if concentration is a factor in the
formation of PAs, as the presence of chaperonins suggests [30], diluting the space in
which the proteins interact lowers the rate of aggregation. In both scenarios, the change
in type is related to a change in the ability of that instance of a particular PA or protein-
containing complex to realize its function. An instance of a particular PCC at t1 may
change type at t2 when a continuant part is added or removed, while altering the ability
of the PCC to realize its function in either direction. Conversely, an instance of a
particular protein aggregate pa1 at t1 does not change type at t2 when a continuant part
is added or removed. Thus the ability of that instance of the particular PA to realize its
function, if any at all, is not affected.
Function is determined by the structural organization of a material entity [12]. A
basic example of this is the denaturation (loss of secondary and tertiary structure) of a
fully folded protein p1 of type R at t1 so that it changes to an instance of polypeptide
type Q at t2. Polypeptides lacking secondary and tertiary structure no longer are of type
‘protein’, and cannot realize their function. So, in this case, the change in ability of an
instance of an entity to realize its function is accompanied by a change in type of that
particular instance.
A second case, where an entity retains its type but cannot realize its function, is also
possible. Post-translational modifications (PTMs) modulate the activity of proteins and
protein-containing entities through induction of conformational changes in the structure
of the entity [31]. While PTMs are an avenue through which conformational (structural)
change occurs, they result in a temporary loss (or gain) of the ability of an instance of an
entity of a particular type to realize its function but do not result in a change in the type
of that instance. In addition to discrepancies in the level of fluidity of the arrangement of
their components, it is along these functional lines that PAs and protein-containing
complexes differentiate—in their respective tendency to change type in response to
various structural alterations as well as changes in ability to realize function.
Our proposed definitions for the terms ‘protein-containing complex’ and ‘protein
aggregate’ are not without issue. Currently, the primary distinguishing feature of the
definition of ‘protein-containing complex’ is the disposal to change type upon
dissociation of a continuant part. However, the current definitions do not address the
differences in maximum possible number of continuant parts which can comprise protein
aggregates versus protein complexes. This is an important distinction the true nature of
which needs to be explored in future work.
Acknowledgments:
Part of the research reported in this publication was supported by the National Center for
Advancing Translational Sciences of the National Institutes of Health under award
number UL1TR001412 to the University at Buffalo. The content is solely the
responsibility of the authors and does not necessarily represent the official views of the
NIH.
References
1. Panov P, Tolovski I, Kostovska A, Tollovski I, Kostovska A. The Neurodegenerative Disease Data
Ontology [Internet]. 2019 [cited 2020 May 10]. Available from:
https://bioportal.bioontology.org/ontologies/NDDO?p=summary
2. Gillepsie T. Neuroscience Information Framework Standard Ontology [Internet]. 2018. 2018.
Available from: https://bioportal.bioontology.org/ontologies/NIFSTD?p=summary
3. Murphy RM. Peptide Aggregation in Neurodegenerative Disease. Annu Rev Biomed Eng. 2002
Aug;4(1):155–74.
4. Wells C, Brennan SE, Keon M, Saksena NK. Prionoid Proteins in the Pathogenesis of
Neurodegenerative Diseases. Front Mol Neurosci [Internet]. 2019 [cited 2019 Dec 6];12:271.
Available from: http://www.ncbi.nlm.nih.gov/pubmed/31780895
5. Davis AA, Leyns CEG, Holtzman DM. Intercellular Spread of Protein Aggregates in
Neurodegenerative Disease. Annu Rev Cell Dev Biol [Internet]. 2018/07/25. 2018 Oct 6;34:545–68.
Available from: https://www.ncbi.nlm.nih.gov/pubmed/30044648
6. Saunders MG, Tempkin J, Weare J, Dinner AR, Roux B, Voth GA. Nucleotide regulation of the
structure and dynamics of G-actin. Biophys J. 2014;106(8):1710–20.
7. Wallings RL, Humble SW, Ward ME, Wade-Martins R. Lysosomal Dysfunction at the Centre of
Parkinson’s Disease and Frontotemporal Dementia/Amyotrophic Lateral Sclerosis. Trends Neurosci
[Internet]. 2019 Dec [cited 2019 Dec 5];42(12):899–912. Available from:
http://www.ncbi.nlm.nih.gov/pubmed/31704179
8. Taguchi Y. Glucosylsphingosine promotes alpha-synuclein pathology in mutant GPA-associated
Parkinson’s disease. J Neurosci. 2017;(37):9617–31.
9. Coico R, Sunshine G. Immunology: A Short Course. 7th ed. John Wiley & Sons, Incorporated; 2015.
67 p.
10. Proteins A. Actin and Actin-Binding Proteins. Cell Biol. 2017;575–91.
11. Pollard TD. Actin and Actin-Binding Proteins. Cold Spring Harb Perspect Biol. 2016;8(8):1–17.
12. Smith B. Basic Formal Ontology 2.0 Specification and User’s Guide [Internet]. 2015. p. 30–6.
Available from: https://github.com/bfo-ontology/BFO/wiki
13. Lamark T, Johansen T. Aggrephagy: Selective disposal of protein aggregates by macroautophagy.
International Journal of Cell Biology. 2012.
14. Wang W, Nema S, Teagarden D. Protein aggregation-Pathways and influencing factors. Vol. 390,
International Journal of Pharmaceutics. 2010. p. 89–99.
15. Michalak W, Tsiamis V, Schwämmle V, Rogowska-Wrzesińska A. ComplexBrowser: A tool for
identification and quantification of protein complexes in large-scale proteomics datasets. Mol Cell
Proteomics. 2019 Aug 25;18(11):2324–34.
16. Marsh JA, Teichmann SA. Structure, Dynamics, Assembly, and Evolution of Protein Complexes.
Annu Rev Biochem. 2015 Jun 2;84(1):551–75.
17. Carbon S, Douglass E, Dunn N, Good B, Harris NL, Lewis SE, et al. The Gene Ontology Resource:
20 years and still GOing strong. Nucleic Acids Res [Internet]. 2019 Jan 8 [cited 2020 Feb
17];47(D1):D330–8. Available from: https://academic.oup.com/nar/article/47/D1/D330/5160994
18. Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, et al. Gene ontology: Tool for
the unification of biology. Vol. 25, Nature Genetics. NIH Public Access; 2000. p. 25–9.
19. Sigurdson CJ, Bartz JC, Nilsson KPR. Tracking protein aggregate interactions. Prion [Internet].
2011/04/01. 2011 Apr [cited 2020 Feb 18];5(2):52–5. Available from:
https://www.ncbi.nlm.nih.gov/pubmed/21597336
20. Seneci P. Chemical Modulators of Protein Misfolding and Neurodegenerative Disease. 2015. 173–
228 p.
21. Taggart JC, Zauber H, Selbach M, Li GW, McShane E. Keeping the Proportions of Protein Complex
Components in Check. Vol. 10, Cell Systems. Cell Press; 2020. p. 125–32.
22. Kalas M, Ison J, Menager H, Schwämmle V. EDAM Ontology [Internet]. 2020 [cited 2020 May 10].
Available from: https://bioportal.bioontology.org/ontologies/EDAM?p=summary
23. Näger PM, Husmann J. Peter van Inwagen : Materialism, Free Will and God [Internet]. Vol. 4. 2018.
1–268 p. Available from: http://link.springer.com/10.1007/978-3-319-70052-6
24. Carbon S, Ireland A, Mungall CJ, Shu S, Marshall B, Lewis S, et al. AmiGO: Online access to
ontology and annotation data. Bioinformatics. 2009;25(2):288–9.
25. Amoutzias G, Van de Peer Y. Single-Gene and Whole-Genome Duplications and the Evolution of
Protein-Protein Interaction Networks. In: Evolutionary Genomics and Systems Biology [Internet].
Hoboken, NJ, USA: John Wiley & Sons, Inc.; 2010 [cited 2020 Feb 7]. p. 413–29. Available from:
http://doi.wiley.com/10.1002/9780470570418.ch19
26. Mintseris J, Weng Z. Structure, Function, and Evolution of Transient and Obligate Protein-protein
interactions. Proc Natl Acad Sci U S A [Internet]. 2005 Aug 2 [cited 2019 Nov 15];102(31):10930–
5. Available from:
https://search.lib.buffalo.edu/discovery/fulldisplay?docid=pnas_s102_31_10930&context=PC&vid
=01SUNY_BUF:everything&lang=en&search_scope=UBSUNY&adaptor=Primo
Central&tab=EverythingUBSUNY&query=any,contains,obligate protein complexes&offset=0
27. Spirin V, Mirny LA. Protein complexes and functional modules in molecular networks. Proc Natl
Acad Sci U S A. 2003 Oct 14;100(21):12123–8.
28. Jansen L, Schulz S. Grains, components and mixtures in biomedical ontologies. J Biomed Semantics.
2011;2(4).
29. Tomii K. Protein Properties. In: Encyclopedia of Bioinformatics and Computational Biology.
Elsevier; 2019. p. 28–33.
30. Skjærven L, Cuellar J, Martinez A, Valpuesta JM. Dynamics, flexibility, and allostery in molecular
chaperonins. Vol. 589, FEBS Letters. Elsevier B.V.; 2015. p. 2522–32.
31. Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P. Molecular Biology of the Cell. 5th ed.
New York, NY: Garland Science; 2008. 389–391 p.