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Allosteric Modulation of Intrinsically Disordered Proteins

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Protein Allostery in Drug Discovery

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1163))

Abstract

The allosteric property of globular proteins is applauded as their intrinsic ability to regulate distant sites, and this property further plays a critical role in a wide variety of cellular regulatory mechanisms. Recent advancements and studies have revealed the manifestation of allostery in intrinsically disordered proteins or regions as allosteric sites present within or mediated by IDP/IDRs facilitates the signaling interactions for various biological mechanisms which would otherwise be impossible for globular proteins to regulate. This thematic review has highlighted the biological outcomes that can be achieved by the mechanism of allosteric regulation of intrinsically disordered proteins or regions. The similar mechanism has been implemented on Adenovirus 5 early region 1A and tumor apoptosis protein p53 in correspondence with other partners in binary and ternary complexes, which are the subject of the current review. Both these proteins regulate once they bind to their partners, consequently, forming either a binary or a ternary complex. Allosteric regulation by IDPs is currently a subject undergoing intense study, and the ongoing research work will ensure a better understanding of precision and efficiency of cellular regulation by them. Allosteric regulation mechanism can also be researched by intrinsically disordered protein-specific force field.

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Abbreviations

ATM:

Ataxia-telangiectasia mutated (gene ATM)

ATR:

Ataxia-telangiectasia and Rad3-related (ATR)

CAK:

CDK-activating kinase

CBP:

CREB-binding protein (CREBBP)

CDC2:

Cell division cycle 2 kinase

CDKs:

Cyclin-dependent kinases (multiple members)

CHK1:

Cell cycle checkpoint kinase 1 (CHEK1)

CHK2:

Cell cycle checkpoint kinase 2 (CHEK2)

CK1:

Casein kinase 1 (multiple isoforms)

CK2:

Casein kinase 2 (multiple isoforms)

CSN:

COP9 signalosome (protein complex)

DNA-PK:

DNA-dependent protein kinase (PRKDC)

ERK2:

p42 mitogen-activated protein kinase (MAPK1)

FACT:

Facilitating chromatin-mediated transcription

HIPK2:

Homeodomain-interacting protein kinase 2

JNK:

Jun N-terminal kinase (MAPK8)

MDM2:

Mouse double-minute 2 homologue

P38:

p38 mitogen-activated protein kinase (MAPK14)

P300:

E1A-binding protein, 300-kDa (EP300)

PCAF:

P300/CBP-associated factor

PKC:

Protein kinase C (multiple isoforms)

PKR:

Double-stranded RNA-dependent protein kinase (PRKR)

PIAS:

Protein inhibitor of activated STAT (multiple isoforms)

PIN1:

Peptidyl-prolyl-cis-trans isomerase 1

RSK2:

Ribosomal S6 kinase 2 (RPS6KA3)

SET9:

SET domain-containing protein 9 (SET9)

STK15:

Serine/threonine protein kinase 15

TAF II250:

TATA-binding protein-associated factor 250-kD (TAF1)

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Acknowledgment

This work was supported by the Center for HPC at Shanghai Jiao Tong University, the National Key Research and Development Program of China (2018YFC0310803 and 2017YFE0103300), the National Natural Science Foundation of China (31770771 and 31620103901), and the Medical Engineering Cross Fund of Shanghai Jiao Tong University (YG2015MS56 and YG2017MS08).

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  1. Ashfaq Ur Rehman and Mueed Ur Rahman contributed equally to this chapter.

Authors and Affiliations

  1. State Key Laboratory of Microbial Metabolism, Department of Bioinformatics and Biostatistics, National Experimental Teaching Center for Life Sciences and Biotechnology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China

    Ashfaq Ur Rehman, Mueed Ur Rahman, Taaha Arshad & Hai-Feng Chen

  2. Department of Biochemistry, Abdul Wali Khan University Mardan, Mardan, Pakistan

    Ashfaq Ur Rehman

  3. Shanghai Center for Bioinformation Technology, Shanghai, China

    Hai-Feng Chen

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  1. Ashfaq Ur Rehman
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  2. Mueed Ur Rahman
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Correspondence to Hai-Feng Chen .

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Editors and Affiliations

  1. Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University, School of Medicine, Shanghai, China

    Jian Zhang

  2. Cancer and Inflammation Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, USA, Sackler Institute of Molecular Medicine, Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

    Ruth Nussinov

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Rehman, A.U., Rahman, M.U., Arshad, T., Chen, HF. (2019). Allosteric Modulation of Intrinsically Disordered Proteins. In: Zhang, J., Nussinov, R. (eds) Protein Allostery in Drug Discovery. Advances in Experimental Medicine and Biology, vol 1163. Springer, Singapore. https://doi.org/10.1007/978-981-13-8719-7_14

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