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 ...

, 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 ...

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 exists and is required for biological function.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 ra ...

. 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 completel ...

. 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 fundame ...

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 phys ...

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 a ...

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 ...

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, res ...

, DNA, RNA 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 ...

). Many

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 ...

, 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 i ...

are gained upon

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 ...

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 ...

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 a ...

C-terminal domains and H4

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 mo ...

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 i ...

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 s ...

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

{{reflist, 35em Protein structure Stereochemistry