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PDBsum entry 4j1y
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References listed in PDB file
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Key reference
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Title
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A molecular switch governs the interaction between the human complement protease c1s and its substrate, Complement c4.
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Authors
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A.J.Perry,
L.C.Wijeyewickrema,
P.G.Wilmann,
M.J.Gunzburg,
L.D'Andrea,
J.A.Irving,
S.S.Pang,
R.C.Duncan,
J.A.Wilce,
J.C.Whisstock,
R.N.Pike.
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Ref.
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J Biol Chem, 2013,
288,
15821-15829.
[DOI no: ]
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PubMed id
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Abstract
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The complement system is an ancient innate immune defense pathway that plays a
front line role in eliminating microbial pathogens. Recognition of foreign
targets by antibodies drives sequential activation of two serine proteases, C1r
and C1s, which reside within the complement Component 1 (C1) complex. Active C1s
propagates the immune response through its ability to bind and cleave the
effector molecule complement Component 4 (C4). Currently, the precise structural
and biochemical basis for the control of the interaction between C1s and C4 is
unclear. Here, using surface plasmon resonance, we show that the transition of
the C1s zymogen to the active form is essential for C1s binding to C4. To
understand this, we determined the crystal structure of a zymogen C1s construct
(comprising two complement control protein (CCP) domains and the serine protease
(SP) domain). These data reveal that two loops (492-499 and 573-580) in the
zymogen serine protease domain adopt a conformation that would be predicted to
sterically abrogate C4 binding. The transition from zymogen to active C1s
repositions both loops such that they would be able to interact with
sulfotyrosine residues on C4. The structure also shows the junction of the CCP1
and CCP2 domains of C1s for the first time, yielding valuable information about
the exosite for C4 binding located at this position. Together, these data
provide a structural explanation for the control of the interaction with C1s and
C4 and, furthermore, point to alternative strategies for developing therapeutic
approaches for controlling activation of the complement cascade.
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