PDBsum entry 1nzi

Hydrolase

PDB id: 1nzi

Contents

Protein chains

155 a.a. *

156 a.a. *

Metals

_MG ×2

_CA ×2

Waters ×288

* Residue conservation analysis

PDB id:

1nzi

Name:

Hydrolase

Title:

Crystal structure of the cub1-egf interaction domain of complement protease c1s

Structure:

Complement c1s component. Chain: a, b. Fragment: calcium-dependent interaction domain. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: c1s. Expressed in: trichoplusia ni. Expression_system_taxid: 7111. Expression_system_cell_line: high five insect cells.

Biol. unit:

Dimer (from PQS)

Resolution:

1.50Å R-factor: 0.216 R-free: 0.234

Authors:

L.A.Gregory,N.M.Thielens,G.J.Arlaud,J.C.Fontecilla-Camps,C.Gaboriaud

Key ref:

L.A.Gregory et al. (2003). X-ray structure of the Ca2+-binding interaction domain of C1s. Insights into the assembly of the C1 complex of complement. J Biol Chem, 278, 32157-32164. PubMed id: 12788922 DOI: 10.1074/jbc.M305175200

Date:

18-Feb-03 Release date: 10-Jun-03

Protein chain

P09871  (C1S_HUMAN) -  Complement C1s subcomponent from Homo sapiens

Seq: 688 a.a.

Struc: 155 a.a.

Protein chain

P09871  (C1S_HUMAN) -  Complement C1s subcomponent from Homo sapiens

Seq: 688 a.a.

Struc: 156 a.a.

Enzyme reactions

• Enzyme class: Chains A, B: E.C.3.4.21.42 - complement subcomponent C1s.
• Reaction: Cleaves component C4 to C4a and C4b (Arg-|-Ala bond), and component C2 to C2a and C2b (Lys(or Arg)-|-Lys bond).

DOI no: 10.1074/jbc.M305175200

J Biol Chem 278:32157-32164 (2003)

PubMed id: 12788922

X-ray structure of the Ca2+-binding interaction domain of C1s. Insights into the assembly of the C1 complex of complement.

L.A.Gregory, N.M.Thielens, G.J.Arlaud, J.C.Fontecilla-Camps, C.Gaboriaud.

ABSTRACT

C1, the complex that triggers the classical pathway of complement, is assembled from two modular proteases C1r and C1s and a recognition protein C1q. The N-terminal CUB1-EGF segments of C1r and C1s are key elements of the C1 architecture, because they mediate both Ca2+-dependent C1r-C1s association and interaction with C1q. The crystal structure of the interaction domain of C1s has been solved and refined to 1.5 A resolution. The structure reveals a head-to-tail homodimer involving interactions between the CUB1 module of one monomer and the epidermal growth factor (EGF) module of its counterpart. A Ca2+ ion is bound to each EGF module and stabilizes both the intra- and inter-monomer interfaces. Unexpectedly, a second Ca2+ ion is bound to the distal end of each CUB1 module, through six ligands contributed by Glu45, Asp53, Asp98, and two water molecules. These acidic residues and Tyr17 are conserved in approximately two-thirds of the CUB repertoire and define a novel, Ca2+-binding CUB module subset. The C1s structure was used to build a model of the C1r-C1s CUB1-EGF heterodimer, which in C1 connects C1r to C1s and mediates interaction with C1q. A structural model of the C1q/C1r/C1s interface is proposed, where the rod-like collagen triple helix of C1q is accommodated into a groove along the transversal axis of the C1r-C1s heterodimer.

Selected figure(s)

Figure 2.
FIG. 2. Homodimeric structure of the CUB1-EGF interaction domain of C1s. A, ribbon plot of a top view of the structure. Molecule A is in red (CUB1 module) and pink (EGF module). Molecule B is in green (CUB1) and blue (EGF). Ca^2^+ ions are represented by golden spheres. Dots represent disordered segments, namely Gly60, Asp61, Thr62, and Phe^123 in monomer A and Glu1, Pro2, and Asn74 in monomer B. C[t] indicates a C-terminal end. B and C, space-filling representations of bottom and side views of the structure. D, stereo view of a representative portion of the electron density map corresponding to the aromatic triad at the dimer interface (contoured at the 1 level).

Figure 3.
FIG. 3. Structure of the C1s CUB1 module. A, superposition of the C1s CUB1 structure (red) on that of aSFP (47) (blue) (stereo view). The Ca^2^+ ion bound to the C1s CUB1 module is represented as a golden sphere. B, stereo view of the Ca^2^+-binding site. Oxygen atoms are shown in red, and nitrogen atoms are in blue. Water molecules are represented as light blue spheres. Ionic and hydrogen bonds are represented by dotted black and blue lines, respectively. C, sequence alignment of various CUB modules including the CUB1 and CUB2 modules of C1s, C1r, MASP-1 and MASP-2, the CUB modules of the spermadhesin family, and selected CUB modules from PCPE, TSG6, BMP-1, and cubilin. All of the sequences are from human proteins, except PSP-I and -II (porcine) and aSFP (bovine). The secondary structure elements (except strands 1 and 2 and loop L1) and the numbering are those of the C1s CUB1 module. Conserved residues defining the CUB domain signature and cysteines are colored blue, those involved in Ca^2^+ binding in C1s are pink, and those involved in the inter-monomer interface are orange.

The above figures are reprinted by permission from the ASBMB: J Biol Chem (2003, 278, 32157-32164) copyright 2003.

Figures were selected by an automated process.