Role of structural disorder in the multi-functionality of flavivirus proteins

ABSTRACT

Introduction

The life cycle of a virus involves interacting with the host cell, entry, hijacking host machinery for viral replication, evading the host’s immune system, and releasing mature virions. However, viruses, being small in size, can only harbor a genome large enough to code for the minimal number of proteins required for the replication and maturation of the virions. As a result, many viral proteins are multifunctional machines that do not directly obey the classic structure-function paradigm. Often, such multifunctionality is rooted in intrinsic disorder that allows viral proteins to interact with various cellular factors and remain functional in the hostile environment of different cellular compartments.

Areas covered

This report covers the classification of flaviviruses, their proteome organization, and the prevalence of intrinsic disorder in the proteomes of different flaviviruses. Further, we have summarized the speculations made about the apparent roles of intrinsic disorder in the observed multifunctionality of flaviviral proteins.

Expert opinion

Small sizes of viral genomes impose multifunctionality on their proteins, which is dependent on the excessive usage of intrinsic disorder. In fact, intrinsic disorder serves as a universal functional tool, weapon, and armor of viruses and clearly plays an important role in their functionality and evolution.

KEYWORDS:

• Intrinsically disordered proteins
• protein function
• protein multifunctionality
• flaviviruses
• viral protein

Article highlights

• Flaviviruses are arthropod-borne human pathogens causing severe diseases

• There are very few vaccines for flaviviruses, and there no drugs targeting these viruses

• Small flaviviral proteome contains multifunctional proteins derived from a single polyprotein

• Life cycle of flaviviruses depends on interaction with multiple host proteins

• Viral proteins have multiple functions and interact with a wide range of host proteins

• Multifunctionality of flaviviral proteins depends on the use of intrinsic disorder

• Structural disorder should be considered in design of anti-flaviviral vaccines and drugs

Declaration of Interests

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

RG is thankful to IYBA award from DBT, Government of India (BT/11/IYBA/2018/06), MHRD-SPARC (SPARC/2018-2019/P37/SL), Science and Engineering Research Board (SERB), India (Grant Number: CRG/2019/005603), and Indian Council of Medical Research (Grant numbers: 58/6/2020/PHA/BMS, 52/04/2020/BIO/BMS). SKK is grateful to ICMR-SRF for funding. AB and TB are thankful to MHRD and DST-INSPIRE for their fellowships.