Structural insights into the pSer/pThr dependent regulation of the SHP2 tyrosine phosphatase in insulin and CD28 signaling

András Zeke (), Tamás Takács, Péter Sok, Krisztina Németh, Klára Kirsch, Péter Egri, Ádám Levente Póti, Isabel Bento, Gábor E. Tusnády and Attila Reményi
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András Zeke: Institute of Enzymology, Research Centre for Natural Sciences
Tamás Takács: Insitute of Enzymology, Research Centre for Natural Sciences
Péter Sok: Institute of Organic Chemistry, Research Centre for Natural Sciences
Krisztina Németh: Institute of Organic Chemistry, Research Centre for Natural Sciences
Klára Kirsch: Institute of Organic Chemistry, Research Centre for Natural Sciences
Péter Egri: Institute of Organic Chemistry, Research Centre for Natural Sciences
Ádám Levente Póti: Institute of Organic Chemistry, Research Centre for Natural Sciences
Isabel Bento: EMBL Outstation Hamburg
Gábor E. Tusnády: Institute of Enzymology, Research Centre for Natural Sciences
Attila Reményi: Institute of Organic Chemistry, Research Centre for Natural Sciences

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: Abstract Serine/threonine phosphorylation of insulin receptor substrate (IRS) proteins is well known to modulate insulin signaling. However, the molecular details of this process have mostly been elusive. While exploring the role of phosphoserines, we have detected a direct link between Tyr-flanking Ser/Thr phosphorylation sites and regulation of specific phosphotyrosine phosphatases. Here we present a concise structural study on how the activity of SHP2 phosphatase is controlled by an asymmetric, dual phosphorylation of its substrates. The structure of SHP2 has been determined with three different substrate peptides, unveiling the versatile and highly dynamic nature of substrate recruitment. What is more, the relatively stable pre-catalytic state of SHP2 could potentially be useful for inhibitor design. Our findings not only show an unusual dependence of SHP2 catalytic activity on Ser/Thr phosphorylation sites in IRS1 and CD28, but also suggest a negative regulatory mechanism that may also apply to other tyrosine kinase pathways as well.

Date: 2022
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DOI: 10.1038/s41467-022-32918-5

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