The crystal structure of the tetrameric human vasohibin‐1–SVBP complex reveals a variable arm region within the structural core

• Published in: Acta crystallographica. Section D, Biological crystallography. Biological crystallography., 2020-10, Vol.76 (10), p.993-1000
• Main Authors: Ikeda, Akihito, Urata, Seia, Ando, Tadashi, Suzuki, Yasuhiro, Sato, Yasufumi, Nishino, Tatsuya
• Format: Article
• Language: English
• Subjects: Angiogenesis; Carboxypeptidase; Catalytic activity; Complex formation; Crystal structure; Dynamic structural analysis; Enzymatic activity; Enzyme activity; Hydrogen bonding; Hydrophobicity; MD simulations; Metastases; microtubule modification; protein complex; Regulatory mechanisms (biology); Research Papers; small vasohibin‐binding protein; Substrates; Tubulin; Tyrosine; VASH1–SVBP complex; vasohibin; X‐ray crystal structure
• ISSN: 2059-7983; 0907-4449; 2059-7983; 1399-0047
• DOI: 10.1107/S2059798320011298

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. Vasohibin‐1 and small vasohibin‐binding protein (SVBP) form an intermolecular heterotetramer in the crystal. The heterotetramer was stabilized by exchange of the conserved N‐terminal region.