TY - JOUR
T1 - The crystal structure of the tetrameric human vasohibin-1-SVBP complex reveals a variable arm region within the structural core
AU - Ikeda, Akihito
AU - Urata, Seia
AU - Ando, Tadashi
AU - Suzuki, Yasuhiro
AU - Sato, Yasufumi
AU - Nishino, Tatsuya
N1 - Funding Information:
We acknowledge support from the collaboration project of the Platform Project for Supporting Drug Discovery and Life Science Research (Basis for Supporting Innovative Drug Discovery and Life Science Research; BINDS) from AMED (Grant No. 1739), NIG-JOINT (Grant Nos. 6A2017, 2A2018 and 85A2019) and the Cooperative Research Program of the Institute for Protein Research, Osaka University (Grant Nos. CR-17-05, CR-18-05 and CR-19-05). This work was supported by a Grant-in-Aid for Scientific Research from the Japanese Society for the Promotion of Science (Grant No. 16K07279).
Publisher Copyright:
© 2020 Ikeda et al.
PY - 2020/10/1
Y1 - 2020/10/1
N2 - Vasohibins regulate angiogenesis, tumor growth, metastasis and neuronal differentiation. They form a complex with small vasohibin-binding protein (SVBP) and show tubulin tyrosine carboxypeptidase activity. Recent crystal structure determinations of vasohibin-SVBP complexes have provided a molecular basis for complex formation, substrate binding and catalytic activity. However, the regulatory mechanism and dynamics of the complex remain elusive. Here, the crystal structure of the VASH1-SVBP complex and a molecular-dynamics simulation study are reported. The overall structure of the complex was similar to previously reported structures. Importantly, however, the structure revealed a domain-swapped heterotetramer that was formed between twofold symmetry-related molecules. This heterotetramerization was stabilized by the mutual exchange of ten conserved N-terminal residues from the VASH1 structural core, which was intramolecular in other structures. Interestingly, a comparison of this region with previously reported structures revealed that the patterns of hydrogen bonding and hydrophobic interactions vary. In the molecular-dynamics simulations, differences were found between the heterotetramer and heterodimer, where the fluctuation of the N-terminal region in the heterotetramer was suppressed. Thus, heterotetramer formation and flexibility of the N-terminal region may be important for enzyme activity and regulation.
AB - Vasohibins regulate angiogenesis, tumor growth, metastasis and neuronal differentiation. They form a complex with small vasohibin-binding protein (SVBP) and show tubulin tyrosine carboxypeptidase activity. Recent crystal structure determinations of vasohibin-SVBP complexes have provided a molecular basis for complex formation, substrate binding and catalytic activity. However, the regulatory mechanism and dynamics of the complex remain elusive. Here, the crystal structure of the VASH1-SVBP complex and a molecular-dynamics simulation study are reported. The overall structure of the complex was similar to previously reported structures. Importantly, however, the structure revealed a domain-swapped heterotetramer that was formed between twofold symmetry-related molecules. This heterotetramerization was stabilized by the mutual exchange of ten conserved N-terminal residues from the VASH1 structural core, which was intramolecular in other structures. Interestingly, a comparison of this region with previously reported structures revealed that the patterns of hydrogen bonding and hydrophobic interactions vary. In the molecular-dynamics simulations, differences were found between the heterotetramer and heterodimer, where the fluctuation of the N-terminal region in the heterotetramer was suppressed. Thus, heterotetramer formation and flexibility of the N-terminal region may be important for enzyme activity and regulation.
KW - MD simulations
KW - VASH1-SVBP complex
KW - X-ray crystal structure
KW - microtubule modification
KW - protein complex
KW - small vasohibin-binding protein
KW - vasohibin
UR - http://www.scopus.com/inward/record.url?scp=85092657789&partnerID=8YFLogxK
U2 - 10.1107/S2059798320011298
DO - 10.1107/S2059798320011298
M3 - Article
C2 - 33021501
AN - SCOPUS:85092657789
SN - 0907-4449
VL - 76
SP - 993
EP - 1000
JO - Acta Crystallographica Section D: Structural Biology
JF - Acta Crystallographica Section D: Structural Biology
ER -