Determination of the molecular reach of the protein tyrosine phosphatase SHP-1

Clemens, Lara; Kutuzov, Mikhail A.; Bayer, Kristina Viktoria; Goyette, Jesse; Allard, Jacques; Dushek, Omer

doi:10.1016/j.bpj.2021.03.019

Cited by 12 publications

(10 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The volume they can explore proximal to the inner leaflet of the membrane is highly restricted, which increases their effective concentration. Estimates for other tethered phosphatase reactions suggest that effective concentrations as high as 1,000 µM are possible ( 37 , 52 ). Therefore, the accelerated unbinding of ZAP70 we have observed in T cells may be a consequence of the combination of CD45 having a high abundance and high catalytic rate and being tethered near its substrates on the membrane.…”

Section: Discussionmentioning

confidence: 99%

Dephosphorylation accelerates the dissociation of ZAP70 from the T cell receptor

Goyette

Depoil

Yang

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

Protein–protein binding domains are critical in signaling networks. Src homology 2 (SH2) domains are binding domains that interact with sequences containing phosphorylated tyrosines. A subset of SH2 domain–containing proteins has tandem domains, which are thought to enhance binding affinity and specificity. However, a trade-off exists between long-lived binding and the ability to rapidly reverse signaling, which is a critical requirement of noise-filtering mechanisms such as kinetic proofreading. Here, we use modeling to show that the unbinding rate of tandem, but not single, SH2 domains can be accelerated by phosphatases. Using surface plasmon resonance, we show that the phosphatase CD45 can accelerate the unbinding rate of zeta chain–associated protein kinase 70 (ZAP70), a tandem SH2 domain–containing kinase, from biphosphorylated peptides from the T cell receptor (TCR). An important functional prediction of accelerated unbinding is that the intracellular ZAP70–TCR half-life in T cells will not be fixed but rather, dependent on the extracellular TCR–antigen half-life, and we show that this is the case in both cell lines and primary T cells. The work highlights that tandem SH2 domains can break the trade-off between signal fidelity (requiring long half-life) and signal reversibility (requiring short half-life), which is a key requirement for T cell antigen discrimination mediated by kinetic proofreading.

show abstract

Section: Discussionmentioning

confidence: 99%

Dephosphorylation accelerates the dissociation of ZAP70 from the T cell receptor

Goyette

Depoil

Yang

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

show abstract

“…This spatial arrangement might allow these receptors to bind SHP1 and SHP2 in the parallel mode. The physiological significance of parallel binding is unclear, but it might increase the molecular reach of the PTPase domain ( Clemens et al, 2021 ; Zhang et al, 2019 ), or avoid potential steric clash with the plasma membrane.…”

Section: Discussionmentioning

confidence: 99%

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

Masubuchi

Cai

et al. 2021

eLife

View full text Add to dashboard Cite

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.

show abstract

“…This spatial arrangement might allow these receptors to bind Shp1 and Shp2 in the parallel mode. The physiological significance of parallel binding is unclear, but it might increase the molecular reach of the PTPase domain 49,50 , or avoid potential steric clash with the plasma membrane.…”

Section: Discussionmentioning

confidence: 99%

Molecular Features Underlying Shp1/Shp2 Discrimination by Immune Checkpoint Receptors

Hui

Masubuchi

et al. 2021

Preprint

View full text Add to dashboard Cite

Numerous inhibitory immunoreceptors operate by recruiting phosphatase effectors Shp1 and Shp2 through conserved motifs ITIM and ITSM. Despite the similarity, these receptors exhibit distinct effector binding specificities, as exemplified by PD-1 and BTLA, which preferentially recruit Shp2 and Shp1 respectively. The molecular basis of Shp1/Shp2 discrimination is unclear. Here, we provide evidence that optimal PD-1 and BTLA binding to both Shp1 and Shp2 occurs via a bivalent, parallel mode that involves both SH2 domains of Shp1/Shp2. Moreover, PD-1 mainly uses its ITSM to discriminate Shp2 from Shp1 via their C-terminal SH2 domains. Supportive of this model, swapping the Shp1-cSH2 with Shp2-cSH2 enabled PD-1:Shp1 association in T cells. In contrast, BTLA primarily utilizes its ITIM to discriminate Shp1 from Shp2 via their N-terminal SH2 domains. Substitution of glycine at pY+1 position of the PD-1-ITIM with alanine, a residue conserved in several Shp1-recruiting receptors, was sufficient to induce PD-1:Shp1 interaction in T cells. Finally, mutagenesis screening shows that Shp1 recruitment 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 general implications for the mechanism of effector discrimination by inhibitory receptors.

show abstract

Determination of the molecular reach of the protein tyrosine phosphatase SHP-1

Cited by 12 publications

References 58 publications

Dephosphorylation accelerates the dissociation of ZAP70 from the T cell receptor

Dephosphorylation accelerates the dissociation of ZAP70 from the T cell receptor

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

Molecular Features Underlying Shp1/Shp2 Discrimination by Immune Checkpoint Receptors

Contact Info

Product

Resources

About