CaltechAUTHORS
Published March 21, 2025 | Version Published
Journal Article Open

Evolving concepts of the protein universe

Creators

  • 1. ROR icon City Of Hope National Medical Center
  • 2. ROR icon California Institute of Technology
  • 3. ROR icon National Center for Biotechnology Information
  • 4. ROR icon University of Florence
  • 5. ROR icon Center for Theoretical Biological Physics
  • 6. ROR icon Rice University
  • 7. ROR icon University of Kent
  • 8. ROR icon University of South Florida
  • 9. ROR icon North Carolina State University
  • 10. W. M. Keck Laboratory for Structural Biology, University of Maryland Institute for Bioscience and Biotechnology Research, Rockville, MD, USA
  • 11. ROR icon University of Maryland, College Park

Abstract

The protein universe is the collection of all proteins on earth from all organisms both extant and extinct. Classical studies on protein folding suggested that proteins exist as a unique three-dimensional conformation that is dictated by the genetic code and is critical for function. In this perspective, we discuss ideas and developments that emerged over the past three decades regarding the protein structure-function paradigm. It is now clear that ordered (active/functional) and disordered/denatured (and hence inactive/non-functional) represent a continuum of states rather than binary states. Some proteins can switch folds without sequence change. Others exist as conformational ensembles lacking defined structure yet play critical roles in many biological processes, including forming membrane-less organelles driven by liquid-liquid phase separation. Numerous diverse proteins harbor segments with the potential to form amyloid fibrils, many of which are functional, and some possess prion-like properties enabling conformation-based transfer of heritable information. Taken together, these developments reveal the remarkable complexity of the protein universe.

Copyright and License

© 2025 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Acknowledgement

We thank Dr. Ariane Helou, California Institute of Technology, for her thoughtful comments on the manuscript and expert edits. To all our peers whose work we were unable to cite due to space limitations, we extend our sincere apology. Work in the Chiti laboratory was supported by the Regione Toscana (Bando Ricerca Salute 2018, PRAMA project) and Ministero dell’Università e Ricerca (projects PNRR PE8 Age-IT and PRIN 2020PBS5MJ). The work done by Joseph W. Schafer and Lauren L. Porter was supported by the Intramural Research Program of the National Library of Medicine, National Institutes of Health (LM202011). Work in the Orban laboratory was supported by NIH R01 GM62154 and GM141290 funding, in the Weninger laboratory by a NIH grant GM132263, and that in the Salgia laboratory by a NIH/NCI Cancer Center Support Grant P30CA033572-40 and a DOD grant HT9425-23-1-0581. Shasha Chong is supported by the NIH/NCI under award number P30CA016042, Pew-Stewart Scholar Award, Searle Scholar Award, The Shurl and Kay Curci Foundation Research Grant, Merkin Innovation Seed Grant, The Mallinckrodt Research Grant, The Margaret E. Early Medical Research Trust Grants, and The Alex’s Lemonade Stand Foundation Innovation Grant under award number 1260879.

Conflict of Interest

The authors declare no competing interests.

Contributions

P.K. and R.S. conceptualized the manuscript; P.K., V.N.U., L.P., J.W.S, T.-F. C., S.C., F.C., M.T., and E.V.K. and wrote the first draft; J.N.O., K.R.W., J.O., F.C., E.V.K., and R.S. contributed substantially by revising the manuscript; All authors approved the submitted version and are fully accountable for every aspect of the work.

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Additional details

Identifiers

PMID
40124498
PMCID
PMC11926713

Funding

Regione Toscana
Bando Ricerca Salute 2018, PRAMA project
Ministero dell'Università e della Ricerca
United States National Library of Medicine
LM202011
National Institutes of Health
R01 GM62154
National Institutes of Health
GM141290
National Institutes of Health
GM132263
National Cancer Institute
P30CA033572-40
United States Department of Defense
HT9425-23-1-0581
National Cancer Institute
P30CA016042
Shurl and Kay Curci Foundation
Mallinckrodt (United States)
Alex's Lemonade Stand Foundation
1260879

Dates

Available
2025-03-04
Version of record

Caltech Custom Metadata

Caltech groups
Division of Chemistry and Chemical Engineering (CCE) , Division of Biology and Biological Engineering (BBE)
Publication Status
Published