Structural studies of cerebral cavernous malformations 2 (CCM2) reveal a folded helical domain at its C-terminus

Oriana S. Fisher; Rong Zhang; Xiaofeng Li; James W. Murphy; Borries Demeler; Titus J. Boggon

doi:10.1016/j.febslet.2012.12.011

Structural studies of cerebral cavernous malformations 2 (CCM2) reveal a folded helical domain at its C-terminus

Oriana S. Fisher
, Rong Zhang
, Xiaofeng Li
, James W. Murphy
, Borries Demeler
, Titus J. Boggon

Chemistry and Biochemistry

Yale University

Research output: Contribution to journal › Article › peer-review

34 Scopus citations

Abstract

Cerebral cavernous malformations (CCM) are neurovascular dysplasias affecting up to 0.5% of the population. Mutations in the CCM2 gene are associated with acquisition of CCM. We identify a previously uncharacterized domain at the C-terminus of CCM2 and determine its 1.9 Å resolution crystal structure. Because this domain is structurally homologous to the N-terminal domain of harmonin, we name it the CCM2 harmonin-homology domain or HHD. CCM2 HHD is observed in two conformations, and we employ analytical ultracentrifugation to test its oligomerization. Additionally, CCM2 HHD contains an unusually long 13-residue 3₁₀ helix. This study provides the first structural characterization of CCM2. Structured summary of protein interactions: CCM2 binds to CCM3 by pull down (View interaction) CCM2 and CCM2 bind by X-ray crystallography (View interaction) CCM2 and CCM2 bind by molecular sieving (View interaction)

Original language	English
Pages (from-to)	272-277
Number of pages	6
Journal	FEBS Letters
Volume	587
Issue number	3
DOIs	https://doi.org/10.1016/j.febslet.2012.12.011
State	Published - Jan 31 2013

Funding

We thank V. Schirf, W. Min, B. Turk, H.J. Lou, K. Draheim, A. Stiegler, W. Liu, N. Alicea-Velázquez, B.H. Ha, J. Chacon, D. Calderwood, J. Ferrullo, and beamlines X25, X29, and NECAT. Grants from NSF (O.S.F.), AHA (X.L.), NIH CA054174 , RR022200 (B.D.), and NSF TG-MCB070038 (B.D.). T.J.B. funded by the NIH.

Funders	Funder number
RR022200, TG-MCB070038
P30CA054174
American Heart Association

Keywords

Cerebral cavernous malformation
Harmonin-homology domain
Protein-protein interaction
Signal transduction
X-ray crystallography

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10.1016/j.febslet.2012.12.011

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title = "Structural studies of cerebral cavernous malformations 2 (CCM2) reveal a folded helical domain at its C-terminus",

abstract = "Cerebral cavernous malformations (CCM) are neurovascular dysplasias affecting up to 0.5\% of the population. Mutations in the CCM2 gene are associated with acquisition of CCM. We identify a previously uncharacterized domain at the C-terminus of CCM2 and determine its 1.9 {\AA} resolution crystal structure. Because this domain is structurally homologous to the N-terminal domain of harmonin, we name it the CCM2 harmonin-homology domain or HHD. CCM2 HHD is observed in two conformations, and we employ analytical ultracentrifugation to test its oligomerization. Additionally, CCM2 HHD contains an unusually long 13-residue 310 helix. This study provides the first structural characterization of CCM2. Structured summary of protein interactions: CCM2 binds to CCM3 by pull down (View interaction) CCM2 and CCM2 bind by X-ray crystallography (View interaction) CCM2 and CCM2 bind by molecular sieving (View interaction)",

keywords = "Cerebral cavernous malformation, Harmonin-homology domain, Protein-protein interaction, Signal transduction, X-ray crystallography",

author = "Fisher, \{Oriana S.\} and Rong Zhang and Xiaofeng Li and Murphy, \{James W.\} and Borries Demeler and Boggon, \{Titus J.\}",

note = "Funding Information: We thank V. Schirf, W. Min, B. Turk, H.J. Lou, K. Draheim, A. Stiegler, W. Liu, N. Alicea-Vel{\'a}zquez, B.H. Ha, J. Chacon, D. Calderwood, J. Ferrullo, and beamlines X25, X29, and NECAT. Grants from NSF (O.S.F.), AHA (X.L.), NIH CA054174 , RR022200 (B.D.), and NSF TG-MCB070038 (B.D.). T.J.B. funded by the NIH. ",

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doi = "10.1016/j.febslet.2012.12.011",

language = "English",

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journal = "FEBS Letters",

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T1 - Structural studies of cerebral cavernous malformations 2 (CCM2) reveal a folded helical domain at its C-terminus

AU - Fisher, Oriana S.

AU - Zhang, Rong

AU - Li, Xiaofeng

AU - Murphy, James W.

AU - Demeler, Borries

AU - Boggon, Titus J.

N1 - Funding Information: We thank V. Schirf, W. Min, B. Turk, H.J. Lou, K. Draheim, A. Stiegler, W. Liu, N. Alicea-Velázquez, B.H. Ha, J. Chacon, D. Calderwood, J. Ferrullo, and beamlines X25, X29, and NECAT. Grants from NSF (O.S.F.), AHA (X.L.), NIH CA054174 , RR022200 (B.D.), and NSF TG-MCB070038 (B.D.). T.J.B. funded by the NIH.

PY - 2013/1/31

Y1 - 2013/1/31

N2 - Cerebral cavernous malformations (CCM) are neurovascular dysplasias affecting up to 0.5% of the population. Mutations in the CCM2 gene are associated with acquisition of CCM. We identify a previously uncharacterized domain at the C-terminus of CCM2 and determine its 1.9 Å resolution crystal structure. Because this domain is structurally homologous to the N-terminal domain of harmonin, we name it the CCM2 harmonin-homology domain or HHD. CCM2 HHD is observed in two conformations, and we employ analytical ultracentrifugation to test its oligomerization. Additionally, CCM2 HHD contains an unusually long 13-residue 310 helix. This study provides the first structural characterization of CCM2. Structured summary of protein interactions: CCM2 binds to CCM3 by pull down (View interaction) CCM2 and CCM2 bind by X-ray crystallography (View interaction) CCM2 and CCM2 bind by molecular sieving (View interaction)

AB - Cerebral cavernous malformations (CCM) are neurovascular dysplasias affecting up to 0.5% of the population. Mutations in the CCM2 gene are associated with acquisition of CCM. We identify a previously uncharacterized domain at the C-terminus of CCM2 and determine its 1.9 Å resolution crystal structure. Because this domain is structurally homologous to the N-terminal domain of harmonin, we name it the CCM2 harmonin-homology domain or HHD. CCM2 HHD is observed in two conformations, and we employ analytical ultracentrifugation to test its oligomerization. Additionally, CCM2 HHD contains an unusually long 13-residue 310 helix. This study provides the first structural characterization of CCM2. Structured summary of protein interactions: CCM2 binds to CCM3 by pull down (View interaction) CCM2 and CCM2 bind by X-ray crystallography (View interaction) CCM2 and CCM2 bind by molecular sieving (View interaction)

KW - Cerebral cavernous malformation

KW - Harmonin-homology domain

KW - Protein-protein interaction

KW - Signal transduction

KW - X-ray crystallography

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DO - 10.1016/j.febslet.2012.12.011

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SN - 0014-5793

VL - 587

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JO - FEBS Letters

JF - FEBS Letters

IS - 3

ER -

Structural studies of cerebral cavernous malformations 2 (CCM2) reveal a folded helical domain at its C-terminus

Abstract

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Keywords

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