Protein codes and mobility together shape cellular function and disease

Henry R Kilgore; Shannon Moreno; Richard A Young

doi:10.1016/j.tibs.2025.10.009

Protein codes and mobility together shape cellular function and disease

Trends Biochem Sci. 2025 Nov 28:S0968-0004(25)00250-6. doi: 10.1016/j.tibs.2025.10.009. Online ahead of print.

Authors

Henry R Kilgore¹, Shannon Moreno², Richard A Young³

Affiliations

¹ Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Current address: Faculty of Pharmaceutical Sciences, The University of British Columbia, 2405 Wesbrook Mall, Vancouver, BC, V6T 1Z3, Canada. Electronic address: hkilgore@wi.mit.edu.
² Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
³ Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Electronic address: young@wi.mit.edu.

PMID: 41318327
DOI: 10.1016/j.tibs.2025.10.009

Abstract

Cells organize their biochemical activities by assembling proteins into both membrane-bound organelles and membrane-less condensates. These compartments enable specialized chemical environments that support unique biochemical functions. Recent evidence indicates that proteins carry encoded instructions for not only protein folding, but also selective distribution into condensate compartments. The dynamic movement of proteins into and within compartments is essential for normal function, while disruptions that reduce protein mobility can impair biochemical rates and cause dysfunction and disease. Here, we review these principles of condensate compartmentalization, emphasizing how encoded protein properties, chemical environments, and dynamic movement shape both cellular health and disease pathology.

Keywords: biomolecular condensates; collision-limited reactions; macromolecular crowding; oxidative stress; protein solvation environments; proteolethargy.

Publication types

Review