Co-Translational Folding of Multi-Domain Proteins

Nandakumar Rajasekaran; Christian M Kaiser

doi:10.3389/fmolb.2022.869027

Co-Translational Folding of Multi-Domain Proteins

Front Mol Biosci. 2022 Apr 20:9:869027. doi: 10.3389/fmolb.2022.869027. eCollection 2022.

Authors

Nandakumar Rajasekaran¹, Christian M Kaiser^{2

3}

Affiliations

¹ CMDB Graduate Program, Johns Hopkins University, Baltimore, MD, United States.
² Department of Biology, Johns Hopkins University, Baltimore, MD, United States.
³ Department of Biophysics, Johns Hopkins University, Baltimore, MD, United States.

Abstract

The majority of proteins in nature are composed of multiple domains connected in a single polypeptide. How these long sequences fold into functional structures without forming toxic misfolds or aggregates is poorly understood. Their folding is inextricably linked to protein synthesis and interactions with cellular machinery, making mechanistic studies challenging. Recent progress has revealed critical features of multi-domain protein folding in isolation and in the context of translation by the ribosome. In this review, we discuss challenges and progress in understanding multi-domain protein folding, and highlight how molecular interactions shape folding and misfolding pathways. With the development of new approaches and model systems, the stage is now set for mechanistically exploring the folding of large multi-domain proteins.

Keywords: co-translational folding; inter-domain interactions; multi-domain proteins; optical tweezers; protein misfolding; ribosome; single-molecule methods.

Publication types

Review

Grants and funding

R01 GM121567/GM/NIGMS NIH HHS/United States