Journal article

Structural and functional analysis of target recognition by the lymphocyte adaptor protein LNK

Rhiannon Morris, Yaoyuan Zhang, Julia Ellyard, Carola G Vinuesa, James M Murphy, Artem Laktyushin, Nadia J Kershaw, Jeffrey J Babon



The SH2B family of adaptor proteins, SH2-B, APS, and LNK are key modulators of cellular signalling pathways. Whilst SH2-B and APS have been partially structurally and biochemically characterised, to date there has been no such characterisation of LNK. Here we present two crystal structures of the LNK substrate recognition domain, the SH2 domain, bound to phosphorylated motifs from JAK2 and EPOR, and biochemically define the basis for target recognition. The LNK SH2 domain adopts a canonical SH2 domain fold with an additional N-terminal helix. Targeted analysis of binding to phosphosites in signalling pathways indicated that specificity is conferred by amino acids one- and three-residues down..

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Awarded by National Health and Medical Research Council (NHMRC) Australia

Awarded by NHMRC IRIISS Grant

Funding Acknowledgements

We sincerely thank the late Prof. Tony Pawson, discoverer of the SH2 domain, who first approached and inspired us to study this protein. We are very grateful to Kazuya Machida for the details of their lnk construct. This work was supported by the National Health and Medical Research Council (NHMRC) Australia (Project grant no. 1122999, Program grant no. 1113577), an NHMRC IRIISS Grant 9000220, and a Victorian State Government Operational Infrastructure Scheme grant. J.J.B. is supported by an NHMRC fellowship. RM was supported by an Australian Postgraduate Award. This research was undertaken in part using the MX2 beamline at the Australian Synchrotron, part of ANSTO, and made use of the Australian Cancer Research Foundation (ACRF) Eiger detector48. Crystallization trials were performed at CSIRO collaborative crystallization centre (C3).