WEHI Wednesday Seminar hosted by Professor Sandra Nicholson
 

Kunlun Li
PhD Student – Nicholson Laboratory, Inflammation division – Infection, Inflammation & Immunity Theme, WEHI (this is a PhD Completion seminar)

Discovery of an exosite on the SOCS2-SH2 domain that enhances SH2 binding to phosphorylated ligands

 

Davis Auditorium

Join via SLIDO enter code #WEHIWednesday

Including Q&A session
 

Tyrosine phosphorylation is a fundamental step in many signal transduction cascades required to mediate cellular processes. The Src homology 2 (SH2) domain forms the largest family of phosphotyrosine recognition domains, with a total of 120 different SH2 domains found in 110 distinct proteins in the human genome. The binding specificities between different SH2 domains and the sequence surrounding the phosphotyrosine motif in individual proteins guarantee the accurate recognition of the target protein and tightly regulated signal transmission. Discovered at WEHI in 1997, Suppressor of Cytokine Signalling 2 (SOCS2) acts as negative regulator of growth hormone (GH) signalling by interacting with phosphotyrosine 595 on the GH receptor through the SOCS2-SH2 domain. Consequently, SOCS2-deficient mice exhibit gigantism.

Kunlun’s PhD project aimed to investigate how the SOCS2-SH2 domain was involved in target recognition. He was able to demonstrate the importance of SH2 recognition of phosphotyrosine in vivo and contributed to the identification of an exosite on the SOCS2-SH2 domain that, when occupied by a peptide (F3), reciprocally enhanced the affinity of the SH2 domain for its canonical phosphorylated ligands. This discovery led to the hypothesis that SOCS2-SH2 recognition of its phosphotyrosine targets could be regulated through protein interaction with the exosite. Using mass spectrometry, Kunlun identified Ring Finger Protein 169 (RNF169) as an exosite-binding protein. Moreover, a predicted alpha-helical peptide derived from RNF169 showed high similarity to F3 and reciprocally enhanced the affinity of the SH2 domain for phosphorylated ligands. The interaction between RNF169 and SOCS2 was further confirmed by proximity ligation assay. SOCS2 and RNF169 are both upregulated in acute myeloid leukemia (AML), with high SOCS2 expression correlating with poor patient prognosis. Kunlun is continuing to investigate the impact of the RNF169:SOCS2 interaction in AML; the pieces of the puzzle are still coming together.

All welcome!