Towards Decoding the Sequence-Based Grammar Governing the Functions of Intrinsically Disordered Protein Regions. Issue 12 (11th June 2021)

• Record Type: Journal Article
• Authors: Chong, Shasha; Mir, Mustafa
• Is Part Of: Journal of molecular biology. Volume 433:Issue 12(2021)
• Publication Date: 2021-06-11
• Subjects: intrinsically disordered regions -- interactions -- biomolecular assemblies -- sequence -- function; IDR intrinsically disordered region -- Pol II RNA polymerase II -- LLPS liquid-liquid phase separation -- NMR nuclear magnetic resonance -- SLiM short linear motif -- PTM post-translational modification -- MoRF molecular recognition feature -- LC low complexity -- NICD Nephrin intracellular domain -- LacO Lac operator -- RPA random-phase-approximation -- SEC-SAXS size exclusion chromatography-coupled small-angle X-ray scattering -- SR dipeptide sequence serine:arginine -- CTD C-terminal domain -- P-TEFb positive transcription elongation factor b -- AS alternative splicing -- ALS amyotrophic lateral sclerosis -- FTD frontotemporal dementia -- Htt huntingtin protein -- PolyQ poly-glutamine -- mHtt disease-causing Htt mutants -- C9ORF72 chromosome 9 open reading frame 72 -- GR dipeptide sequence glycine:arginine -- PR dipeptide sequence proline:arginine; Molecular biology -- Periodicals; Biology -- Periodicals; Biochemistry -- Periodicals; Bacteriology -- Periodicals; Molecular Biology -- Periodicals; Biochemistry -- Periodicals; Biologie moléculaire -- Périodiques; Biologie -- Périodiques; Biochimie -- Périodiques; Moleculaire biologie; Biochemistry; Biology; Molecular biology; Periodicals; 572.805
• DOI: 10.1016/j.jmb.2020.11.023
• Languages: English
• ISSNs: 0022-2836

Abstract

Graphical abstract: Highlights: IDRs form biomolecular assemblies via multivalent and selective interactions. Molecular features derived from amino acid sequences can predict protein disorder. Sequence features of IDRs impact their selective interactions and functions. Modifications of IDR sequences modulate their interactions and functions. Sequence features of IDRs predict their assembly formation behaviors and functions. Abstract: A substantial portion of the proteome consists of intrinsically disordered regions (IDRs) that do not fold into well-defined 3D structures yet perform numerous biological functions and are associated with a broad range of diseases. It has been a long-standing enigma how different IDRs successfully execute their specific functions. Further putting a spotlight on IDRs are recent discoveries of functionally relevant biomolecular assemblies, which in some cases form through liquid-liquid phase separation. At the molecular level, the formation of biomolecular assemblies is largely driven by weak, multivalent, but selective IDR-IDR interactions. Emerging experimental and computational studies suggest that the primary amino acid sequences of IDRs encode a variety of their interaction behaviors. In this review, we focus on findings and insights that connect sequence-derived features of IDRs to their conformations, propensities to form biomolecular assemblies, selectivity of interaction partners, functions in the context of physiology and disease, and regulation of function. We also discuss directions of future research to facilitate establishing a comprehensive sequence-function paradigm that will eventually allow prediction of selective interactions and specificity of function mediated by IDRs.