Modulation of Weak Protein‐Protein Interaction by Molecular Crowding. Issue 29 (18th October 2017)

• Record Type: Journal Article
• Authors: Srinivasan, P.
• Is Part Of: ChemistrySelect. Volume 2:Issue 29(2017)
• Page Start: 9563
• Page End: 9569
• Publication Date: 2017-10-18
• Subjects: Binding thermodynamics -- Conformational dynamics -- Molecular crowding -- Protein modification; Chemistry -- Periodicals; 540.5
• DOI: 10.1002/slct.201701904
• Languages: English
• ISSNs: 2365-6549

Abstract

Abstract: Many membrane‐targeted signaling proteins undergo self‐associated homo‐oligomerization for triggering a cascade of downstream events in cells. Unraveling thermodynamic properties influencing homo‐oligomerization of large proteins in cell environment would bring valuable insight into biological signaling. Using Stromal Interaction Molecule 1 (STIM1) and Calcium Release‐Activated Calcium Channel Protein (ORAI1) coupling machinery as a model system, here I present invitro biophysical and biochemical evidences to explicate activation mechanism of STIM1 and its stabilization from energetics standpoint. Analyses of molecular arrangements using entropy and free energy estimates indicate homo‐oligomerization by molecular crowding is energetically favorable to form ordered structures of STIM1 to interact with ORAI1. A corollary of this finding is activated human STIM1 'puncta' observed in over‐expressed cell biology experiment perhaps represents a more ordered non‐equilibrium state at which leucines of the cytoplasmic STIM1 fragment are shielded from solvent by energetically efficient molecular crowding. Abstract : Several membrane proteins undergo homo‐oligomerization to initiate diverse signaling cascades in cells. Human Stromal Interaction Molecule1 (hSTIM1) is one such candidate that self‐associates within Endoplasmic Reticulum membrane to trigger calcium influx in cells. Using invitro biochemical, cell biological and computational studies, here I show that hSTIM1 homo‐oligomerization by localized molecular crowding is an energetically favorable mechanism to achieve an increased order for hSTIM1 activation in cells.