Date Published: April 10, 2019
Publisher: Public Library of Science
Author(s): Sandra Berndt, Vsevolod V. Gurevich, T. M. Iverson, Titus J. Boggon.
Lyn kinase (Lck/Yes related novel protein tyrosine kinase) belongs to the family of Src-related non-receptor tyrosine kinases. Consistent with physiological roles in cell growth and proliferation, aberrant function of Lyn is associated with various forms of cancer, including leukemia, breast cancer and melanoma. Here, we determine a 1.3 Å resolution crystal structure of the polyproline-binding SH3 regulatory domain of human Lyn kinase, which adopts a five-stranded β-barrel fold. Mapping of cancer-associated point mutations onto this structure reveals that these amino acid substitutions are distributed throughout the SH3 domain and may affect Lyn kinase function distinctly.
Lyn kinase (Lck/Yes related novel protein tyrosine kinase) is a Src-family kinase organized into four domains. These include an N-terminal unique domain (also known as SH4 domain), two adapter domains (SH3 and SH2) and C-terminal kinase domain (also known as SH1 domain). Src-family kinase activity is conformationally regulated via distinct interactions between these domains. In the inactive state, the SH3 domain binds to the linker between the SH2 domain and the kinase domain, keeping the kinase in a closed (inactive) conformation . In the active state the SH2 and SH3 domains interact with effectors proteins . This releases the kinase domain and in the resulting open (active) conformation the kinase domain can phosphorylate its substrates [3, 4].
The crystal structure of the Lyn kinase SH3 domain improves the molecular understanding of the regulatory mechanism of the Src family kinases. The mapped cancer-associated mutations in the SH3 domain identify how different regions of this domain affect protein function.