![Sic1](https://upload.wikimedia.org/wikipedia/commons/0/0f/Sic1.png)
Fuzzy complexes are
protein complexes
A protein complex or multiprotein complex is a group of two or more associated polypeptide chains. Protein complexes are distinct from multienzyme complexes, in which multiple catalytic domains are found in a single polypeptide chain.
Protein c ...
, where
structural
A structure is an arrangement and organization of interrelated elements in a material object or system, or the object or system so organized. Material structures include man-made objects such as buildings and machines and natural objects such a ...
ambiguity
Ambiguity is the type of meaning in which a phrase, statement or resolution is not explicitly defined, making several interpretations plausible. A common aspect of ambiguity is uncertainty. It is thus an attribute of any idea or statement ...
or
multiplicity
Multiplicity may refer to: In science and the humanities
* Multiplicity (mathematics), the number of times an element is repeated in a multiset
* Multiplicity (philosophy), a philosophical concept
* Multiplicity (psychology), having or using multi ...
exists and is required for biological
function
Function or functionality may refer to:
Computing
* Function key, a type of key on computer keyboards
* Function model, a structured representation of processes in a system
* Function object or functor or functionoid, a concept of object-oriente ...
.
[Fuxreiter, M. & Tompa, P. (2011) Fuzziness: Structural Disorder in Protein Complexes Austin, New York.] Alteration, truncation or removal of
conformationally ambiguous regions impacts the activity of the corresponding
complex
Complex commonly refers to:
* Complexity, the behaviour of a system whose components interact in multiple ways so possible interactions are difficult to describe
** Complex system, a system composed of many components which may interact with each ...
.
Fuzzy complexes are generally formed by
intrinsically disordered proteins
In molecular biology, an intrinsically disordered protein (IDP) is a protein that lacks a fixed or ordered three-dimensional structure, typically in the absence of its macromolecular interaction partners, such as other proteins or RNA. IDPs rang ...
.
Structural multiplicity usually underlies functional multiplicity of protein complexes
following a
fuzzy logic
Fuzzy logic is a form of many-valued logic in which the truth value of variables may be any real number between 0 and 1. It is employed to handle the concept of partial truth, where the truth value may range between completely true and completely ...
. Distinct binding modes of the
nucleosome
A nucleosome is the basic structural unit of DNA packaging in eukaryotes. The structure of a nucleosome consists of a segment of DNA wound around eight histone proteins and resembles thread wrapped around a spool. The nucleosome is the fundamen ...
are also regarded as a special case of fuzziness.
Historical background
For almost 50 years
molecular biology
Molecular biology is the branch of biology that seeks to understand the molecular basis of biological activity in and between cells, including biomolecular synthesis, modification, mechanisms, and interactions. The study of chemical and physi ...
was based on two dogmas: (i) equating biological function of the protein with a unique three-dimensional
structure
A structure is an arrangement and organization of interrelated elements in a material object or system, or the object or system so organized. Material structures include man-made objects such as buildings and machines and natural objects such as ...
and (ii) assuming exquisite specificity in protein
complexes. Specificity/selectivity is ensured by unambiguous set of
interactions
Interaction is action that occurs between two or more objects, with broad use in philosophy and the sciences. It may refer to:
Science
* Interaction hypothesis, a theory of second language acquisition
* Interaction (statistics)
* Interactions o ...
formed between the protein and its ligand (another
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
,
DNA,
RNA
Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and deoxyribonucleic acid ( DNA) are nucleic acids. Along with lipids, proteins, and carbohydra ...
or
small molecule
Within the fields of molecular biology and pharmacology, a small molecule or micromolecule is a low molecular weight (≤ 1000 daltons) organic compound that may regulate a biological process, with a size on the order of 1 nm. Many drugs ar ...
). Many
protein complexes
A protein complex or multiprotein complex is a group of two or more associated polypeptide chains. Protein complexes are distinct from multienzyme complexes, in which multiple catalytic domains are found in a single polypeptide chain.
Protein c ...
however, contain functionally important/critical regions, which remain highly dynamic in the complex or adopt different
conformations.
This phenomenon is defined fuzziness. The most pertinent example is the
cyclin-dependent kinase inhibitor
A cyclin-dependent kinase inhibitor protein is a protein which inhibits the enzyme cyclin-dependent kinase (CDK). Several function as tumor suppressor proteins. Cell cycle progression is delayed or stopped by cyclin-dependent kinase inhibitors, ...
Sic1
Sic1, a protein, is a stoichiometric inhibitor of Cdk1-Clb (B-type cyclins) complexes in the budding yeast ''Saccharomyces cerevisiae''. Because B-type cyclin-Cdk1 complexes are the drivers of S-phase initiation, Sic1 prevents premature S-phase en ...
, which binds to the SCF subunit of
Cdc4 in a
phosphorylation
In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...
dependent manner.
No regular
secondary structures
Secondary may refer to: Science and nature
* Secondary emission, of particles
** Secondary electrons, electrons generated as ionization products
* The secondary winding, or the electrical or electronic circuit connected to the secondary winding ...
are gained upon
phosphorylation
In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...
and the different phosphorylation sites interchange in the complex.
Classification of fuzzy complexes
Structural ambiguity in protein complexes covers a wide spectrum.
In a polymorphic complex, the protein adopts two or more different conformations upon binding to the same partner, and these conformations can be resolved.
Clamp,
flanking
and random complexes
are dynamic, where ambiguous conformations interchange with each other and cannot be resolved.
Interactions
Interaction is action that occurs between two or more objects, with broad use in philosophy and the sciences. It may refer to:
Science
* Interaction hypothesis, a theory of second language acquisition
* Interaction (statistics)
* Interactions o ...
in fuzzy complexes are usually mediated by
short motifs.
Flanking regions are tolerant to sequence changes as long as the
amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...
composition is maintained, for example in case of linker
histone
In biology, histones are highly basic proteins abundant in lysine and arginine residues that are found in eukaryotic cell nuclei. They act as spools around which DNA winds to create structural units called nucleosomes. Nucleosomes in turn are wr ...
C-terminal domains
and H4
histone
In biology, histones are highly basic proteins abundant in lysine and arginine residues that are found in eukaryotic cell nuclei. They act as spools around which DNA winds to create structural units called nucleosomes. Nucleosomes in turn are wr ...
N-terminal domains.
Regulatory pathways via fuzzy regions
Fuzzy regions modulate the conformational equilibrium
or flexibility
of the binding interface via
transient interactions.
Dynamic regions can also compete with binding sites
or tether them to the target.
Modifications of fuzzy regions by further interactions,
or
posttranslational modifications
Post-translational modification (PTM) is the covalent and generally enzymatic modification of proteins following protein biosynthesis. This process occurs in the endoplasmic reticulum and the golgi apparatus. Proteins are synthesized by ribosom ...
impact
binding affinity
In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. The etymology stems from ''ligare'', which means 'to bind'. In protein-ligand binding, the ligand is usually a mol ...
or specificity.
Alternative splicing
Alternative splicing, or alternative RNA splicing, or differential splicing, is an alternative splicing process during gene expression that allows a single gene to code for multiple proteins. In this process, particular exons of a gene may be ...
can modulate the length of fuzzy regions resulting in context-dependent binding (e.g.
tissue-specificity) on the complex.
EGF/
MAPK
A mitogen-activated protein kinase (MAPK or MAP kinase) is a type of protein kinase that is specific to the amino acids serine and threonine (i.e., a serine/threonine-specific protein kinase). MAPKs are involved in directing cellular responses to ...
,
TGF-β
Transforming growth factor beta (TGF-β) is a multifunctional cytokine belonging to the transforming growth factor superfamily that includes three different mammalian isoforms (TGF-β 1 to 3, HGNC symbols TGFB1, TGFB2, TGFB3) and many other sign ...
and
WNT/Wingless signaling pathways
Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events, most commonly protein phosphorylation catalyzed by protein kinases, which ultimately results in a cellular ...
employ tissue-specific fuzzy regions.
References
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Protein structure
Stereochemistry