20th-banner-rev.png

Albany 2019: 20th Conversation - Abstracts

category image Albany 2019
Conversation 20
June 11-15 2019
Adenine Press (2019)

How nature harnesses entropy to tune protein function

How evolution shapes the conformational landscape of a protein to tune a specific function is poorly understood. Protein evolution is constrained by the stability of the folded, native state. Despite this, many proteins contain intrinsically disordered (ID) peptide segments. In fact, 44% of human proteins contain ID segments >30 residues in length. The majority of these segments have no known function and are often removed to facilitate structural studies. Here we show that an ID segment can enhance the affinity of an effector binding site by modifying the dynamics of an allosteric network. The enhanced affinity does not depend on the sequence or charge of the ID segment. Instead, changes in effector binding affinity can be accurately predicted based on segment length alone. Using a combination of transient state kinetics, hydrogen-deuterium exchange mass spectrometry, thermal denaturation studies, computer simulation and crystal structure analysis, we show that the ID segment alters the energy landscape of a folded protein to favor the allosteric response. Our evidence shows that the ID segment generates an entropic force that can rectify the conformational ensemble of a protein to favor a specific functional state. Thus, the persistence of intrinsic disorder in the proteome may reflect the evolution of low complexity structural elements that can tune a specific protein function.

References

Keul, N.D., Oruganty, K., Bergman, E.T.S., Beattie, N.R., McDonald, W.E., Kadirvelraj, R., Gross, M.L., Phillips, R.S., Harvey, S.C. and Wood, Z.A. (2018). The entropic force generated by intrinsically disordered segments tunes protein function. Nature, 563, p.584.

Zachary A. Wood 1
Nicholas D. Keul 1
Krishnadev Oruganty 2
Elizabeth T. Schaper Bergman 5
Nathaniel R. Beattie 1
Weston E. McDonald 1
Renuka Kadirvelraj 1
Michael L. Gross 5
Robert S. Phillips 3
Stephen C. Harvey 4

1 Department of Biochemistry and Molecular Biology
University of Georgia
Athens, GA, USA

2 Department of Biomedical Engineering
University of Michigan
Ann Arbor, MI, USA

3 Department of Chemistry
Washington University in St. Louis,
St. Louis, MO, USA.

4 Department of Chemistry
University of Georgia
Athens, GA, USA

5 Department of Biochemistry and Biophysics
University of Pennsylvania
Philadelphia, PA

Ph: (706) 583-0304
Email: zaw@uga.edu