PDBsum entry 6f1c

Hydrolase

PDB id: 6f1c

Contents

Protein chains

291 a.a.

276 a.a.

Ligands

NAG-NAG-BMA-MAN-GAL-MAN

NAG-NAG-BMA-MAN-MAN

NAG-NAG-BMA ×2

NAG ×2

Metals

_NA ×6

_CA ×12

PDB id:

6f1c

Name:

Hydrolase

Title:

C1rc1s complex

Structure:

Complement c1r subcomponent. Chain: a, c. Synonym: complement component 1 subcomponent r. Engineered: yes. Complement c1s subcomponent. Chain: d, b. Synonym: c1 esterase,complement component 1 subcomponent s. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: c1r. Expressed in: cricetulus griseus. Expression_system_taxid: 10029. Expression_system_cell_line: dxb11. Gene: c1s.

Resolution:

4.20Å R-factor: 0.250 R-free: 0.305

Authors:

J.O.M.Almitairi,U.Venkatraman Girija,C.M.Furze,X.Simpson-Gray, F.Badakshi,J.E.Marshall,D.A.Mitchell,P.C.E.Moody,R.Wallis

Key ref:

J.O.M.Almitairi et al. (2018). Structure of the C1r-C1s interaction of the C1 complex of complement activation. Proc Natl Acad Sci U S A, 115, 768-773. PubMed id: 29311313

Date:

21-Nov-17 Release date: 17-Jan-18

Protein chains

P00736  (C1R_HUMAN) -  Complement C1r subcomponent from Homo sapiens

Seq: 705 a.a.

Struc: 291 a.a.

Protein chains

P09871  (C1S_HUMAN) -  Complement C1s subcomponent from Homo sapiens

Seq: 688 a.a.

Struc: 276 a.a.

Enzyme reactions

• Enzyme class 2: Chains A, C: E.C.3.4.21.41 - complement subcomponent C1r.
• Reaction: Selective cleavage of Lys(or Arg)-|-Ile bond in complement subcomponent C1s to form the active form of C1s (EC 3.4.21.42).
• Enzyme class 3: Chains D, 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).

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

Proc Natl Acad Sci U S A 115:768-773 (2018)

PubMed id: 29311313

Structure of the C1r-C1s interaction of the C1 complex of complement activation.

J.O.M.Almitairi, U.Venkatraman Girija, C.M.Furze, X.Simpson-Gray, F.Badakshi, J.E.Marshall, W.J.Schwaeble, D.A.Mitchell, P.C.E.Moody, R.Wallis.

ABSTRACT

The multiprotein complex C1 initiates the classical pathway of complement activation on binding to antibody-antigen complexes, pathogen surfaces, apoptotic cells, and polyanionic structures. It is formed from the recognition subcomponent C1q and a tetramer of proteases C1r₂C1s₂as a Ca²⁺-dependent complex. Here we have determined the structure of a complex between the CUB1-EGF-CUB2 fragments of C1r and C1s to reveal the C1r-C1s interaction that forms the core of C1. Both fragments are L-shaped and interlock to form a compact antiparallel heterodimer with a Ca²⁺from each subcomponent at the interface. Contacts, involving all three domains of each protease, are more extensive than those of C1r or C1s homodimers, explaining why heterocomplexes form preferentially. The available structural and biophysical data support a model of C1r₂C1s₂in which two C1r-C1s dimers are linked via the catalytic domains of C1r. They are incompatible with a recent model in which the N-terminal domains of C1r and C1s form a fixed tetramer. On binding to C1q, the proteases become more compact, with the C1r-C1s dimers at the center and the six collagenous stems of C1q arranged around the perimeter. Activation is likely driven by separation of the C1r-C1s dimer pairs when C1q binds to a surface. Considerable flexibility in C1s likely facilitates C1 complex formation, activation of C1s by C1r, and binding and activation of downstream substrates C4 and C4b-bound C2 to initiate the reaction cascade.