Proteins with H-bond packing defects are highly interactive with lipid bilayers: Implications for amyloidogenesis

doi:10.1073/pnas.0335642100

Proteins with H-bond packing defects are highly interactive with lipid bilayers: Implications for amyloidogenesis

Ariel Fernández*,†,‡,§,¶ and
R. Stephen Berry§,‖

^*Institute for Biophysical Dynamics, University of Chicago, Chicago, IL 60637; ^†Institute for Protein Research, Osaka University, 3-2 Yamadaoka, Suita, Osaka 565, Japan; and ^‖James Franck Institute and Department of Chemistry, University of Chicago, Chicago, IL 60637

Edited by S. Walter Englander, University of Pennsylvania School of Medicine, Swarthmore, PA, and approved December 10, 2002 (received for review September 17, 2002)

Abstract

We noticed that disease-related amyloidogenic proteins and especially cellular prion proteins have the highest proportion of incompletely desolvated backbone H bonds among soluble proteins. Such bonds are vulnerable to water attack and thus represent structural weaknesses. We have measured the adsorption of proteins onto phospholipid bilayers and found a strong correlation between the extent of underwrapping of backbone H bonds in the native structure of a protein and its extent of deposition on the bilayer: the less the H bond wrapping, the higher the propensity for protein–bilayer binding. These observations support the proposition that soluble proteins with amyloidogenic propensity and membrane proteins share a pervasive building motif: the underwrapped H bonds. Whereas in membrane proteins, this motif does not signal a structural vulnerability, in soluble proteins, it is responsible for their reactivity.

Footnotes

↵ ‡ On leave from Instituto de Matemática, Universidad Nacional del Sur-Consejo Nacional de Investigaciones Científicas y Técnicas de Argentina, Bahía Blanca 8000, Argentina.
↵ § To whom correspondence may be addressed. E-mail: ariel{at}uchicago.edu or berry{at}uchicago.edu.
↵ ¶ Present address: Department of Computer Science, Institute for Biophysical Dynamics, University of Chicago, 1100 East 58th Street, Chicago, IL 60637-1581.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations:

HB,

H bond;

Hb,

hemoglobin;

UWHB,

underwrapped HB