TY - JOUR
T1 - Crystal structure of the catalytic domain of Haspin, an atypical kinase implicated in chromatin organization
AU - Villa, Fabrizio
AU - Capasso, Paola
AU - Tortorici, Marcello
AU - Forneris, Federico
AU - De Marco, Ario
AU - Mattevi, Andrea
AU - Musacchio, Andrea
PY - 2009/12/1
Y1 - 2009/12/1
N2 - Haspin, a nuclear and chromosome-associated serine/threonine (S/T) kinase, is responsible for mitotic phosphorylation of Thr-3 of histone H3. Haspin bears recognizable similarity to the eukaryotic protein kinase (ePK) fold, but its sequence is highly divergent and there is therefore considerable interest in its structural organization. We report the 2.15-Å crystal structure of the kinase domain of human Haspin. The ePK fold of Haspin contains an array of insertions and deletions. The structure illustrates how Haspin escapes the classical activation scheme of most other kinases. The αC helix, which bears a conserved glutamate that is essential for catalysis, adopts its final active conformation within the small lobe of the kinase. It is sandwiched between an α-helical insertion that precedes the kinase domain, and the activation segment, which adopts an unprecedented conformation. The activation segment, which does not contain phosphorylatable residues, packs against an unusually structured αEF helix. Significantly extruded from the core of the fold, it forms an extensive plateau, hosting several residues implicated in substrate binding. Overall, the structure of the Haspin kinase domain reveals an active conformation that is poised for substrate recognition and phosphorylation in the absence of external regulators.
AB - Haspin, a nuclear and chromosome-associated serine/threonine (S/T) kinase, is responsible for mitotic phosphorylation of Thr-3 of histone H3. Haspin bears recognizable similarity to the eukaryotic protein kinase (ePK) fold, but its sequence is highly divergent and there is therefore considerable interest in its structural organization. We report the 2.15-Å crystal structure of the kinase domain of human Haspin. The ePK fold of Haspin contains an array of insertions and deletions. The structure illustrates how Haspin escapes the classical activation scheme of most other kinases. The αC helix, which bears a conserved glutamate that is essential for catalysis, adopts its final active conformation within the small lobe of the kinase. It is sandwiched between an α-helical insertion that precedes the kinase domain, and the activation segment, which adopts an unprecedented conformation. The activation segment, which does not contain phosphorylatable residues, packs against an unusually structured αEF helix. Significantly extruded from the core of the fold, it forms an extensive plateau, hosting several residues implicated in substrate binding. Overall, the structure of the Haspin kinase domain reveals an active conformation that is poised for substrate recognition and phosphorylation in the absence of external regulators.
KW - Activation segment
KW - Centromere
KW - Chromosome segregation
KW - Histone H3
KW - Mitosis
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U2 - 10.1073/pnas.0908485106
DO - 10.1073/pnas.0908485106
M3 - Article
C2 - 19918049
AN - SCOPUS:73949140419
VL - 106
SP - 20204
EP - 20209
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 48
ER -