Fuzzy complex

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NMR structure of the cyclin-dependent kinase inhibitor Sic1 with the ubiquitin ligase Cdc4 (grey). Out of the nine phosphorylation sites of Sic 1 (spheres) the contacts with T45 and S76 are shown (orange and blue). Sic1.png
NMR structure of the cyclin-dependent kinase inhibitor Sic1 with the ubiquitin ligase Cdc4 (grey). Out of the nine phosphorylation sites of Sic 1 (spheres) the contacts with T45 and S76 are shown (orange and blue).
The fuzzy linker region (shown by dotted line) of the Ultrabithorax transcription factor (orange) connects the homeodomain with the Extradenticle homeodomain (blue) (PDB code 1bi). Alternative splicing modulates the length of the fuzzy region and thus its DNA (grey) binding affinity. Other regulatory fuzzy regions of Ultrabithorax are also shown by dotted lines. Ubx.png
The fuzzy linker region (shown by dotted line) of the Ultrabithorax transcription factor (orange) connects the homeodomain with the Extradenticle homeodomain (blue) (PDB code 1bi). Alternative splicing modulates the length of the fuzzy region and thus its DNA (grey) binding affinity. Other regulatory fuzzy regions of Ultrabithorax are also shown by dotted lines.

Fuzzy complexes are protein complexes, where structural ambiguity or multiplicity exists and is required for biological function. [1] [2] Alteration, truncation or removal of conformationally ambiguous regions impacts the activity of the corresponding complex. [3] [4] [5] Fuzzy complexes are generally formed by intrinsically disordered proteins. [6] [7] Structural multiplicity usually underlies functional multiplicity of protein complexes [8] [9] [10] following a fuzzy logic. Distinct binding modes of the nucleosome are also regarded as a special case of fuzziness. [11] [12]

Contents

Historical background

For almost 50 years molecular biology was based on two dogmas: (i) equating biological function of the protein with a unique three-dimensional structure and (ii) assuming exquisite specificity in protein complexes. Specificity/selectivity is ensured by unambiguous set of interactions formed between the protein and its ligand (another protein, DNA, RNA or small molecule). Many protein complexes however, contain functionally important/critical regions, which remain highly dynamic in the complex or adopt different conformations. [13] This phenomenon is defined fuzziness. The most pertinent example is the cyclin-dependent kinase inhibitor Sic1, which binds to the SCF subunit of Cdc4 in a phosphorylation dependent manner. [14] No regular secondary structures are gained upon phosphorylation and the different phosphorylation sites interchange in the complex. [15]

Classification of fuzzy complexes

Structural ambiguity in protein complexes covers a wide spectrum. [1] In a polymorphic complex, the protein adopts two or more different conformations upon binding to the same partner, and these conformations can be resolved. [16] Clamp, [17] flanking [18] [19] and random complexes [20] [21] are dynamic, where ambiguous conformations interchange with each other and cannot be resolved. Interactions in fuzzy complexes are usually mediated by short motifs. [22] Flanking regions are tolerant to sequence changes as long as the amino acid composition is maintained, for example in case of linker histone C-terminal domains [23] and H4 histone N-terminal domains. [24]

Regulatory pathways via fuzzy regions

Fuzzy regions modulate the conformational equilibrium [25] or flexibility [3] [26] of the binding interface via transient interactions. [27] Dynamic regions can also compete with binding sites [28] or tether them to the target. [29] Modifications of fuzzy regions by further interactions, [8] [30] or posttranslational modifications [31] [32] impact binding affinity or specificity. Alternative splicing can modulate the length of fuzzy regions resulting in context-dependent binding (e.g. tissue-specificity) on the complex. [33] [34] [35] EGF/MAPK, TGF-β and WNT/Wingless signaling pathways employ tissue-specific fuzzy regions.

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<span class="mw-page-title-main">Insulin receptor</span> Cell receptor found in humans

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<span class="mw-page-title-main">Androgen receptor</span> Mammalian protein found in humans

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<span class="mw-page-title-main">Intrinsically disordered proteins</span> Protein without a fixed 3D structure

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<span class="mw-page-title-main">Glucocorticoid receptor</span> Receptor to which cortisol and other glucocorticoids bind

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<span class="mw-page-title-main">Paxillin</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">GAB2</span> Protein-coding gene in the species Homo sapiens

GRB2-associated-binding protein 2 also known as GAB2 is a protein that in humans is encoded by the GAB2 gene.

<span class="mw-page-title-main">CDC42</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">RELA</span> Protein-coding gene in the species Homo sapiens

Transcription factor p65 also known as nuclear factor NF-kappa-B p65 subunit is a protein that in humans is encoded by the RELA gene.

<span class="mw-page-title-main">HMGA1</span> Protein-coding gene in the species Homo sapiens

High-mobility group protein HMG-I/HMG-Y is a protein that in humans is encoded by the HMGA1 gene.

<span class="mw-page-title-main">TRIM28</span> Protein-coding gene in the species Homo sapiens

Tripartite motif-containing 28 (TRIM28), also known as transcriptional intermediary factor 1β (TIF1β) and KAP1, is a protein that in humans is encoded by the TRIM28 gene.

<span class="mw-page-title-main">GTF2I</span> Protein-coding gene in the species Homo sapiens

General transcription factor II-I is a protein that in humans is encoded by the GTF2I gene.

<span class="mw-page-title-main">STXBP1</span> Protein-coding gene in the species Homo sapiens

Syntaxin-binding protein 1 is a protein that in humans is encoded by the STXBP1 gene. This gene encodes a syntaxin-binding protein. The encoded protein appears to play a role in release of neurotransmitters via regulation of syntaxin, a transmembrane attachment protein receptor. Mutations in this gene have been associated with neurological disorders including epilepsy, intellectual disability, and movement disorders.

<span class="mw-page-title-main">NCK2</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">TEAD1</span> Protein-coding gene in the species Homo sapiens

Transcriptional enhancer factor TEF-1 also known as TEA domain family member 1 (TEAD1) and transcription factor 13 (TCF-13) is a protein that in humans is encoded by the TEAD1 gene. TEAD1 was the first member of the TEAD family of transcription factors to be identified.

<span class="mw-page-title-main">PDK3</span> Protein-coding gene in the species Homo sapiens

Pyruvate dehydrogenase lipoamide kinase isozyme 3, mitochondrial is an enzyme that in humans is encoded by the PDK3 gene. It codes for an isozyme of pyruvate dehydrogenase kinase.The pyruvate dehydrogenase (PDH) complex is a nuclear-encoded mitochondrial multienzyme complex that catalyzes the overall conversion of pyruvate to acetyl-CoA and CO2. It provides the primary link between glycolysis and the tricarboxylic acid (TCA) cycle, and thus is one of the major enzymes responsible for the regulation of glucose metabolism. The enzymatic activity of PDH is regulated by a phosphorylation/dephosphorylation cycle, and phosphorylation results in inactivation of PDH. The protein encoded by this gene is one of the four pyruvate dehydrogenase kinases that inhibits the PDH complex by phosphorylation of the E1 alpha subunit. This gene is predominantly expressed in the heart and skeletal muscles. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.

<span class="mw-page-title-main">Cyclin K</span> Protein-coding gene in the species Homo sapiens

Cyclin-K is a protein that in humans is encoded by the CCNK gene.

<span class="mw-page-title-main">Serine/arginine-rich splicing factor 1</span> Protein-coding gene in the species Homo sapiens

Serine/arginine-rich splicing factor 1 (SRSF1) also known as alternative splicing factor 1 (ASF1), pre-mRNA-splicing factor SF2 (SF2) or ASF1/SF2 is a protein that in humans is encoded by the SRSF1 gene. ASF/SF2 is an essential sequence specific splicing factor involved in pre-mRNA splicing. SRSF1 is the gene that codes for ASF/SF2 and is found on chromosome 17. The resulting splicing factor is a protein of approximately 33 kDa. ASF/SF2 is necessary for all splicing reactions to occur, and influences splice site selection in a concentration-dependent manner, resulting in alternative splicing. In addition to being involved in the splicing process, ASF/SF2 also mediates post-splicing activities, such as mRNA nuclear export and translation.

<span class="mw-page-title-main">Gcn2</span>

GCN2 is a serine/threonine-protein kinase that senses amino acid deficiency through binding to uncharged transfer RNA (tRNA). It plays a key role in modulating amino acid metabolism as a response to nutrient deprivation.

References

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