Molecular features underlying differential SHP1/SHP2 binding of immune checkpoint receptors

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Abstract

A large number of inhibitory receptors recruit SHP1 and/or SHP2, tandem-SH2-containing phosphatases, through phosphotyrosine-based motifs ITIM and ITSM. Despite the similarity, these receptors exhibit differential effector binding specificities, as exemplified by the immune checkpoint receptors PD-1 and BTLA, which preferentially recruit SHP2 and SHP1 respectively. The molecular basis by which structurally similar receptors discriminate SHP1 and SHP2 is unclear. Here, we provide evidence that human PD-1 and BTLA optimally bind to SHP1 and SHP2 via a bivalent, parallel mode that involves both SH2 domains of SHP1 or SHP2. PD-1 mainly uses its ITSM to prefer SHP2 over SHP1 via their C-terminal SH2 domains (cSH2): swapping SHP1-cSH2 with SHP2-cSH2 enabled PD-1:SHP1 association in T cells. In contrast, BTLA primarily utilizes its ITIM to prefer SHP1 over SHP2 via their N-terminal SH2 domains (nSH2). The ITIM of PD-1, however, appeared to be de-emphasized due to a glycine at pY+1 position. Substitution of this glycine with alanine, a residue conserved in BTLA and several SHP1-recruiting receptors, was sufficient to induce PD-1:SHP1 interaction in T cells. Finally, structural simulation and mutagenesis screening showed that SHP1 recruitment activity exhibits a bell-shaped dependence on the side chain volume of the pY+1 residue of ITIM. Collectively, we provide a molecular interpretation of the SHP1/SHP2-binding specificities of PD-1 and BTLA, with implications for the mechanisms of a large family of therapeutically relevant receptors.

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All data generated or analysed during this study are included in the manuscript and supporting file

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Xiaozheng Xu

University of California San Diego, La Jolla, United States

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0001-6888-4285
Takeya Masubuchi

University of California San Diego, La Jolla, United States

Competing interests
No competing interests declared.
Qixu Cai

Hong Kong University of Science and Technology, Hong Kong, China

Competing interests
Qixu Cai, QC conducted the structural modeling and simulations.

"This ORCID iD identifies the author of this article:" 0000-0002-4525-4261
Yunlong Zhao

University of California San Diego, La Jolla, United States

Competing interests
No competing interests declared.
Enfu Hui

University of California San Diego, La Jolla, United States

For correspondence
enfuhui@ucsd.edu

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0001-7876-2783

Funding

National Cancer Institute (R37 CA239072-03)

Enfu Hui

Pew Charitable Trusts

Enfu Hui

Searle Scholars Program

Enfu Hui

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.