The molecular basis for cellular function of intrinsically disordered protein regions

Holehouse, Alex S.; Kragelund, Birthe B.

doi:10.1038/s41580-023-00673-0

Cited by 95 publications

(66 citation statements)

References 443 publications

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“…By comparing our previously identified de novo genes with gene duplicates across well-ordered evolutionary timescales (Zhang, et al 2019), we observed striking features that the median proportion of intrinsically disordered regions (IDRs) is 88%, indicating disorder as a predominant characteristic for these proteins over a period of 1-2 million years. The structural versatility of IDRs could confer special molecular advantages for de novo proteins, allowing them to adapt to almost every cellular compartment and perform various functions, including transcription, nuclear transport, RNA binding, signaling, and cell division (Holehouse and Kragelund 2023). For instance, numerous RNA binding proteins and transcription factors, which are known to bind nucleic acids and mediate protein-RNA or protein-DNA interactions, contain IDRs (Brodsky, et al 2020).…”

Section: Discussionmentioning

confidence: 99%

One million years of solitude: the rapid evolution of de novo protein structure and complex

Chen,

Li,

Xia

et al. 2023

Preprint

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Recent studies have established that de novo genes, evolving from non-coding sequences, enhance protein diversity through a stepwise process. However, the pattern and rate of their structural evolution over time remain unclear. Here, we addressed these issues within a short evolutionary timeframe (∼1 million years for 97% of rice de novo genes). We found that de novo genes evolve faster than gene duplicates in the intrinsic disordered regions (IDRs, such as random coils), secondary structural elements (such as α-helix and β-strand), hydrophobicity, and molecular recognition features (MoRFs). Specifically, we observed an 8-14% decay in random coils and IDR lengths per million years per protein, and a 2.3-6.5% increase in structured elements, hydrophobicity, and MoRFs. These patterns of structural evolution align with changes in amino acid composition over time. We also revealed significantly higher positive charges but smaller molecular weights for de novo proteins than duplicates. Tertiary structure predictions demonstrated that most de novo proteins, though not typically well-folded on their own, readily form low-energy and compact complexes with extensive residue contacts and conformational flexibility, suggesting “a faster-binding” scenario in de novo proteins to promote interaction. Our findings illuminate the rapid evolution of protein structure in the early life of de novo proteins in rice genome, originating from noncoding sequences, highlighting their quick transformation into active, complex-forming components within a remarkably short evolutionary timeframe.

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Section: Discussionmentioning

confidence: 99%

One million years of solitude: the rapid evolution of de novo protein structure and complex

Chen,

Li,

Xia

et al. 2023

Preprint

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“…During interphase, condensin II is repressed by MCPH1 which binds via a SLiM to the NCAPG equivalent, NCAPG2 22 , while the cohesin NCAPG equivalent subunit, STAG1/2, is bound by SLiMs found in WAPL, promoting cohesin unloading, CTCF, resulting in stalling/localisation and SGO1, protecting centromeric cohesin 35,46 . In many of these examples the binding of the SLiM is just one of multiple interactions, for example the cysteine rich region of KIF4A also necessary for condensin I binding in cells 25 , and avidity contributing to bind is a common feature of SLiM interactions 47 . Hence, this work and the work of others demonstrates that SLiMs binding HAWK subunits of the SMC complexes condensin and cohesin is a conserved mechanism, resulting in diverse regulatory outcomes (Figure 4F).…”

Section: Discussionmentioning

confidence: 99%

Molecular Mechanism of Condensin I Activation by KIF4A

Cutts,

Tetiker,

Kim

et al. 2024

Preprint

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During mitosis, the condensin I and II complexes compact chromatin into chromosomes. Loss of the chromokinesin, KIF4A, results in reduced condensin I chromosome association. However, the molecular mechanism behind this phenotype is unknown. Here, we show that KIF4A binds directly to condensin I HAWK subunit, NCAPG, via a conserved disordered short linear motif (SLiM) found in its C-terminal tail. KIF4A binding directly competes with two auto-inhibitory interactions in condensin I, mediated by SLiMs found in the N-terminus of NCAPH and the C-terminus of NCAPD2, which bind sites that overlap with KIF4A binding on NCAPG. Addition of the KIF4A SLiM peptide alone is sufficient to stimulate condensin ATPase and DNA loop extrusion activity. We also identify SLiMs in known yeast condensin interactors, Sgo and Lrs4, that bind yeast Ycg1, the HAWK equivalent to NCAPG. Our findings, together with previous work on condensin II and cohesin, demonstrate that SLiMs binding to HAWK subunits is a conserved mechanism of regulation in SMC complexes.

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“…Disorder has a key involvement in interactions of IDPs/IDRs with other proteins/nucleic acids (Alterovitz et al, 2020; Cheng et al, 2007; Dunker et al, 2001, 2005; Dunker, Brown, Lawson, Iakoucheva, & Obradovic, 2002; Hegyi et al, 2007; Hsu et al, 2012, 2013; Huang et al, 2012; Oldfield et al, 2005, 2008; Oldfield & Dunker, 2014; Peng et al, 2014; Toth‐Petroczy et al, 2008; Uversky et al, 2005; Vacic, Oldfield, et al, 2007; van der Lee et al, 2014). Being conformationally malleable and adaptable and being readily tunable by their structural and chemical context, IDPs/IDRs extend the repertoire of macromolecular interactions and serve as ideal responders to regulatory cues (Holehouse & Kragelund, 2023). Furthermore, the larger interacting surface area of IDPs/IDRs (as compared to structured proteins and domains of similar protein lengths) maybe a key importance of disorder in cellular biology.…”

Section: Interactions Of Idps/idrs With Other Proteins and Surfaces I...mentioning

confidence: 99%

Protein structure–function continuum model: Emerging nexuses between specificity, evolution, and structure

Gupta,

Uversky

2024

Protein Science

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The rationale for replacing the old binary of structure–function with the trinity of structure, disorder, and function has gained considerable ground in recent years. A continuum model based on the expanded form of the existing paradigm can now subsume importance of both conformational flexibility and intrinsic disorder in protein function. The disorder is actually critical for understanding the protein–protein interactions in many regulatory processes, formation of membrane‐less organelles, and our revised notions of specificity as amply illustrated by moonlighting proteins. While its importance in formation of amyloids and function of prions is often discussed, the roles of intrinsic disorder in infectious diseases and protein function under extreme conditions are also becoming clear. This review is an attempt to discuss how our current understanding of protein function, specificity, and evolution fit better with the continuum model. This integration of structure and disorder under a single model may bring greater clarity in our continuing quest for understanding proteins and molecular mechanisms of their functionality.

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The molecular basis for cellular function of intrinsically disordered protein regions

Cited by 95 publications

References 443 publications

One million years of solitude: the rapid evolution of de novo protein structure and complex

One million years of solitude: the rapid evolution of de novo protein structure and complex

Molecular Mechanism of Condensin I Activation by KIF4A

Protein structure–function continuum model: Emerging nexuses between specificity, evolution, and structure

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