Crystal structure and functional characterization of the complement regulator MBL/ficolin-associated protein-1 (MAP-1)
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Crystal structure and functional characterization of the complement regulator MBL/ficolin-associated protein-1 (MAP-1). / Skjoedt, Mikkel-Ole; Roversi, Pietro; Hummelshøj, Tina; Palarasah, Yaseelan; Rosbjerg, Anne; Johnson, Steven; Lea, Susan M; Garred, Peter.
In: Journal of Biological Chemistry, Vol. 287, 2012, p. 32913-32921.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Crystal structure and functional characterization of the complement regulator MBL/ficolin-associated protein-1 (MAP-1)
AU - Skjoedt, Mikkel-Ole
AU - Roversi, Pietro
AU - Hummelshøj, Tina
AU - Palarasah, Yaseelan
AU - Rosbjerg, Anne
AU - Johnson, Steven
AU - Lea, Susan M
AU - Garred, Peter
PY - 2012
Y1 - 2012
N2 - The human lectin complement pathway activation molecules comprise MBL, ficolin-1, -2 and -3, in complex with associated serine proteases MASP-1, -2 and -3, and the non-enzymatic sMAP. Recently, a novel plasma protein named MBL/ficolin associated protein-1 (MAP-1) was identified in humans. This protein is the result of a differential splicing of the MASP1 gene and includes the major part of the heavy chain, but lacks the serine protease domain. We investigated the direct interactions of MAP-1 and MASP-3 with ficolin-3 and MBL using surface plasmon resonance and found affinities around 5 nM and 2.5 nM, respectively. We studied structural aspects of MAP-1 and could show by multi-angle laser light scattering that MAP-1 forms a calcium-dependent homo-dimer in solution. We were able to determine the crystal structure of MAP-1, which also contains a head-to-tail dimer approximately 146 Angstrom long. This structure of MAP-1 also enables modeling and assembly of the MASP-1 molecule in its entirety. Finally we found that MAP-1 competes with all three MASPs for ligand binding and is able to mediate a strong dose dependent inhibitory effect on the lectin pathway activation, as measured by levels of C3 and C9.
AB - The human lectin complement pathway activation molecules comprise MBL, ficolin-1, -2 and -3, in complex with associated serine proteases MASP-1, -2 and -3, and the non-enzymatic sMAP. Recently, a novel plasma protein named MBL/ficolin associated protein-1 (MAP-1) was identified in humans. This protein is the result of a differential splicing of the MASP1 gene and includes the major part of the heavy chain, but lacks the serine protease domain. We investigated the direct interactions of MAP-1 and MASP-3 with ficolin-3 and MBL using surface plasmon resonance and found affinities around 5 nM and 2.5 nM, respectively. We studied structural aspects of MAP-1 and could show by multi-angle laser light scattering that MAP-1 forms a calcium-dependent homo-dimer in solution. We were able to determine the crystal structure of MAP-1, which also contains a head-to-tail dimer approximately 146 Angstrom long. This structure of MAP-1 also enables modeling and assembly of the MASP-1 molecule in its entirety. Finally we found that MAP-1 competes with all three MASPs for ligand binding and is able to mediate a strong dose dependent inhibitory effect on the lectin pathway activation, as measured by levels of C3 and C9.
U2 - 10.1074/jbc.M112.386680
DO - 10.1074/jbc.M112.386680
M3 - Journal article
C2 - 22854970
VL - 287
SP - 32913
EP - 32921
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
ER -
ID: 48449009