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Original Articles

Structure-Based Identification, Characterization, and Disruption of Human Securin-Binding SH3 Domains in Lung Cancer

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Pages 231-236 | Received 23 Jan 2016, Accepted 22 Apr 2016, Published online: 21 May 2016
 

ABSTRACT

The human securin is an oncogenic transcription factor that has been found to promote migration and invasion of lung cancer and many other tumors. The protein contains a PxxP motif that can be recognized and bound by diverse cellular partners via Src homology (SH3) domain to regulate biological and pathological events. The motif is covered by a decapeptide segment 161LGPPSPVKMP170 (SecPeptide) as the potential binding site of SH3 domains. Here, we attempted to systemically identify the SH3 binding partners of human securin in lung cancer and to characterize the intermolecular interaction between SecPeptide and the identified SH3 domains. A bioinformatics protocol that integrated literature curation, complex structural modeling, and binding affinity analysis was described to perform systematic search against an array of SH3-containing proteins involved in lung cancer signaling pathway and, consequently, three putative domains, namely GRB2, CRK, and RasGAP, were identified that have high potential to recognize and bind SecPeptide. The molecular mechanism and biological implication underlying the intermolecular interaction between these domains and SecPetide were investigated at structural and energetic level. Surface plasmon resonance assay revealed a high or moderate affinity of SecPeptide and its two mutants binding to CRK-SH3 domain with dissociation constants Kd = 79.8, 24.2, and 64.6 µM, respectively.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the article.

This work was supported by the Nanjing Chest Hospital and the Affiliated Wujin Hospital of Jiangsu University.

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