Peptide-Binding Domains: Are Limp Handshakes Safest?

Niall J. Haslam and Denis C. Shields^*

UCD Complex and Adaptive Systems Laboratory, UCD School of Medicine and Medical Sciences, and UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland.

Abstract: Interactions between short peptides within proteins and peptide-binding domains can trigger many important cell signaling processes, and their interactions are typically of modest affinity. A study showed that this modest affinity appears to be favored by evolution. They used phage display selection to discover "superbinder" Src Homology 2 (SH2) domains, which bound peptides with much stronger affinity than naturally occurring SH2 domains. These superbinder domains had strong biological effects, such as blocking cell signaling. Although the superbinders had higher affinity, this did not appear to reduce their specificity. In contrast, SH2-binding peptides from bacterial pathogens have evolved to exhibit promiscuity of binding to multiple SH2 domains, carried within effector proteins that subvert signaling upon entry into the mammalian cell. Because there are many potential peptide binders of the SH2 domain found in numerous human proteins, modest affinity not only may optimize transient signaling mediated by reversible interactions but also may minimize off-target deleterious binding effects. The stage is set for a more thorough evaluation of the specificity and off-target impact of both naturally occurring and artificial domains and peptides. This may help define both targets and reagents for therapeutic intervention in key signaling processes mediated by short peptides.

* Corresponding author. E-mail: denis.shields{at}ucd.ie

The editors suggest the following Related Resources on Science sites:

In Science Signaling

RESEARCH ARTICLES
Biochemistry
Superbinder SH2 Domains Act as Antagonists of Cell Signaling

Tomonori Kaneko, Haiming Huang, Xuan Cao, Xing Li, Chengjun Li, Courtney Voss, Sachdev S. Sidhu, and Shawn S. C. Li (25 September 2012)
Sci. Signal. 5 (243), ra68. [DOI: 10.1126/scisignal.2003021]
 |  Editor's Summary »  |  Abstract »  |  Full Text »  |  PDF »  |  Supplementary Materials »

RESEARCH ARTICLES
Evolution
The SH2 Domain–Containing Proteins in 21 Species Establish the Provenance and Scope of Phosphotyrosine Signaling in Eukaryotes

Bernard A. Liu, Eshana Shah, Karl Jablonowski, Andrew Stergachis, Brett Engelmann, and Piers D. Nash (6 December 2011)
Sci. Signal. 4 (202), ra83. [DOI: 10.1126/scisignal.2002105]
 |  Editor's Summary »  |  Abstract »  |  Full Text »  |  PDF »  |  Supplementary Materials »

RESEARCH ARTICLES
Structural Biology
Loops Govern SH2 Domain Specificity by Controlling Access to Binding Pockets

Tomonori Kaneko, Haiming Huang, Bing Zhao, Lei Li, Huadong Liu, Courtney K. Voss, Chenggang Wu, Martin R. Schiller, and Shawn Shun-Cheng Li (4 May 2010)
Sci. Signal. 3 (120), ra34. [DOI: 10.1126/scisignal.2000796]
 |  Editor's Summary »  |  Abstract »  |  Full Text »  |  PDF »  |  Supplementary Materials »  |  Interactive Figures »