Cold-Shock Domains-Abundance, Structure, Properties, and Nucleic-Acid Binding.

Udo Heinemann,Yvette Roske

doi:10.3390/cancers13020190

Abstract

Simple SummaryProteins are composed of compact domains, often of known three-dimensional structure, and natively unstructured polypeptide regions. The abundant cold-shock domain is among the set of canonical nucleic acid-binding domains and conserved from bacteria to man. Proteins containing cold-shock domains serve a large variety of biological functions, which are mostly linked to DNA or RNA binding. These functions include the regulation of transcription, RNA splicing, translation, stability and sequestration. Cold-shock domains have a simple architecture with a conserved surface ideally suited to bind single-stranded nucleic acids. Because the binding is mostly by non-specific molecular interactions which do not involve the sugar-phosphate backbone, cold-shock domains are not strictly sequence-specific and do not discriminate reliably between DNA and RNA. Many, but not all functions of cold shock-domain proteins in health and disease can be understood based of the physical and structural properties of their cold-shock domains.The cold-shock domain has a deceptively simple architecture but supports a complex biology. It is conserved from bacteria to man and has representatives in all kingdoms of life. Bacterial cold-shock proteins consist of a single cold-shock domain and some, but not all are induced by cold shock. Cold-shock domains in human proteins are often associated with natively unfolded protein segments and more rarely with other folded domains. Cold-shock proteins and domains share a five-stranded all-antiparallel β-barrel structure and a conserved surface that binds single-stranded nucleic acids, predominantly by stacking interactions between nucleobases and aromatic protein sidechains. This conserved binding mode explains the cold-shock domains’ ability to associate with both DNA and RNA strands and their limited sequence selectivity. The promiscuous DNA and RNA binding provides a rationale for the ability of cold-shock domain-containing proteins to function in transcription regulation and DNA-damage repair as well as in regulating splicing, translation, mRNA stability and RNA sequestration.

Highlights

Proteins are made of compact domains with defined three-dimensional folding and of natively unstructured polypeptide segments
We focus on the common structural, biophysical and nucleic acid-binding properties of these evolutionarily related domains which share a conserved geometry of binding single-stranded DNA or RNA and limited sequence or nucleic acid-type selectivity
This study suggested a role of YBX1 in mRNA splicing by recruitment of splicing factors to certain splice sites [148]

Summary

Introduction

Proteins are made of compact domains with defined three-dimensional folding and of natively unstructured polypeptide segments. A recent review of CSD-containing proteins [7] directed its focus on their domain structure and sequence motifs in interacting nucleic acids. The cold-inducible RNA-binding protein CIRBP serves a well-documented role in circadian regulation [43], but its RNA association is mediated by an RNA-recognition motif (RRM) and not by a CSD [44]. Cold shock domain-containing protein E1 (CSDE1), known as Upstream of NRas (UNR), contains multiple CSDs suggesting a role as multivalent nucleic acid-binding protein. Cold shock domain-containing protein C2 (CSDC2), known as PIPPin (after a sequence motif inside its CSD), is a mammalian brain-specific protein that binds to histone mRNA and is thought to play a role in the regulation of brain development. PpCSP1 is one of three paralogous PpCSP proteins [92]

Structure of Cold-Shock Domains

Cold-Shock Domain-Binding to Nucleic Acids

Method Method

RNA Binding

Method

Conclusions