title: Structure-Based Identification, Characterization, and Disruption of Human Securin-Binding SH3 Domains in Lung Cancer.
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 (161)LGPPSPVKMP(170) (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.
authors.affiliation: a Department of Thoracic Surgery , Nanjing Chest Hospital , Nanjing , China.
authors.forename: Keping
authors.initials: K
authors.lastname: Wang
authors.affiliation: b Departments of Respiratory , Affiliated Wujin Hospital of Jiangsu University , Changzhou , China.
authors.forename: Tiefeng
authors.initials: T
authors.lastname: Qiu
authors.affiliation: c Department of Medical Oncology , Affiliated Wujin Hospital of Jiangsu University , Changzhou , China.
authors.forename: Xianwen
authors.initials: X
authors.lastname: Li
mesh_terms: D020816:Amino Acid Motifs; D001665:Binding Sites; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008175:Lung Neoplasms / Q000378:metabolism*; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D064249:Securin / Q000737:chemistry* / Q000378:metabolism*; D013329:Structure-Activity Relationship; D018909:src Homology Domains
chemical_list: D010455:Peptides; D064249:Securin
keywords: Human securin; Lung cancer; Oncology; Peptide; SH3 domain