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

A large number of inhibitory receptors recruit SHP1 and/or SHP2, tandem-SH2-containing phosphatases through phosphotyrosine-based motifs immunoreceptor tyrosine-based inhibitory motif (ITIM) and immunoreceptor tyrosine-based switch motif (ITSM). Despite the similarity, these receptors exhibit differ...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Xiaozheng Xu, Takeya Masubuchi, Qixu Cai, Yunlong Zhao, Enfu Hui
Formato:	article
Lenguaje:	EN
Publicado:	eLife Sciences Publications Ltd 2021
Materias:	PD-1 BTLA shp1 shp2 ITIM ITSM Medicine R Science Q Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/1a356497723b4fa1bd2c40c892beaad4
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:1a356497723b4fa1bd2c40c892beaad4
record_format	dspace
spelling	oai:doaj.org-article:1a356497723b4fa1bd2c40c892beaad42021-11-30T11:19:24ZMolecular features underlying differential SHP1/SHP2 binding of immune checkpoint receptors10.7554/eLife.742762050-084Xe74276https://doaj.org/article/1a356497723b4fa1bd2c40c892beaad42021-11-01T00:00:00Zhttps://elifesciences.org/articles/74276https://doaj.org/toc/2050-084XA large number of inhibitory receptors recruit SHP1 and/or SHP2, tandem-SH2-containing phosphatases through phosphotyrosine-based motifs immunoreceptor tyrosine-based inhibitory motif (ITIM) and immunoreceptor tyrosine-based switch motif (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 molecular 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.Xiaozheng XuTakeya MasubuchiQixu CaiYunlong ZhaoEnfu HuieLife Sciences Publications LtdarticlePD-1BTLAshp1shp2ITIMITSMMedicineRScienceQBiology (General)QH301-705.5ENeLife, Vol 10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	PD-1 BTLA shp1 shp2 ITIM ITSM Medicine R Science Q Biology (General) QH301-705.5
spellingShingle	PD-1 BTLA shp1 shp2 ITIM ITSM Medicine R Science Q Biology (General) QH301-705.5 Xiaozheng Xu Takeya Masubuchi Qixu Cai Yunlong Zhao Enfu Hui Molecular features underlying differential SHP1/SHP2 binding of immune checkpoint receptors
description	A large number of inhibitory receptors recruit SHP1 and/or SHP2, tandem-SH2-containing phosphatases through phosphotyrosine-based motifs immunoreceptor tyrosine-based inhibitory motif (ITIM) and immunoreceptor tyrosine-based switch motif (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 molecular 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.
format	article
author	Xiaozheng Xu Takeya Masubuchi Qixu Cai Yunlong Zhao Enfu Hui
author_facet	Xiaozheng Xu Takeya Masubuchi Qixu Cai Yunlong Zhao Enfu Hui
author_sort	Xiaozheng Xu
title	Molecular features underlying differential SHP1/SHP2 binding of immune checkpoint receptors
title_short	Molecular features underlying differential SHP1/SHP2 binding of immune checkpoint receptors
title_full	Molecular features underlying differential SHP1/SHP2 binding of immune checkpoint receptors
title_fullStr	Molecular features underlying differential SHP1/SHP2 binding of immune checkpoint receptors
title_full_unstemmed	Molecular features underlying differential SHP1/SHP2 binding of immune checkpoint receptors
title_sort	molecular features underlying differential shp1/shp2 binding of immune checkpoint receptors
publisher	eLife Sciences Publications Ltd
publishDate	2021
url	https://doaj.org/article/1a356497723b4fa1bd2c40c892beaad4
work_keys_str_mv	AT xiaozhengxu molecularfeaturesunderlyingdifferentialshp1shp2bindingofimmunecheckpointreceptors AT takeyamasubuchi molecularfeaturesunderlyingdifferentialshp1shp2bindingofimmunecheckpointreceptors AT qixucai molecularfeaturesunderlyingdifferentialshp1shp2bindingofimmunecheckpointreceptors AT yunlongzhao molecularfeaturesunderlyingdifferentialshp1shp2bindingofimmunecheckpointreceptors AT enfuhui molecularfeaturesunderlyingdifferentialshp1shp2bindingofimmunecheckpointreceptors
_version_	1718406668596805632

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

Ejemplares similares