CCP

Domain abundant in complement control proteins; SUSHI repeat; short complement-like repeat (SCR)

• SMART accession number: SM00032
• Description: The complement control protein (CCP) modules (also known as short consensus repeats SCRs or SUSHI repeats) contain approximately 60 amino acid residues and have been identified in several proteins of the complement system. A missense mutation in seventh CCP domain causes deficiency of the b subunit of factor XIII.
• Interpro abstract (IPR000436):

  Sushi domains are also known as Complement control protein (CCP) modules, or short consensus repeats (SCR), exist in a wide variety of complement and adhesion proteins. The structure is known for this domain, it is based on a beta-sandwich arrangement; one face made up of three beta-strands hydrogen-bonded to form a triple-stranded region at its centre and the other face formed from two separate beta-strands [(PUBMED:1829116)].

  CD21 (also called C3d receptor, CR2, Epstein Barr virus receptor or EBV-R) is the receptor for EBV and for C3d, C3dg and iC3b. Complement components may activate B cells through CD21. CD21 is part of a large signal-transduction complex that also involves CD19, CD81, and Leu13.

  Some of the proteins in this group are responsible for the molecular basis of the blood group antigens, surface markers on the outside of the red blood cell membrane. Most of these markers are proteins, but some are carbohydrates attached to lipids or proteins [Reid M.E., Lomas-Francis C. The Blood Group Antigen FactsBook Academic Press, London / San Diego, (1997)]. Complement decay-accelerating factor (Antigen CD55) belongs to the Cromer blood group system and is associated with Cr(a), Dr(a), Es(a), Tc(a/b/c), Wd(a), WES(a/b), IFC and UMC antigens. Complement receptor type 1 (C3b/C4b receptor) (Antigen CD35) belongs to the Knops blood group system and is associated with Kn(a/b), McC(a), Sl(a) and Yk(a) antigens.

There are 16471 CCP domains in 3438 proteins in SMART's nrdb database.

Literature (relevant references for this domain)

Primary literature is listed below; Automatically-derived, secondary literature is also avaliable.

• Hashiguchi T, Ichinose A
• Molecular and cellular basis of deficiency of the b subunit for factor XIII secondary to a Cys430-Phe mutation in the seventh Sushi domain.
• J Clin Invest. 1995; 95: 1002-8

We studied the defect responsible for deficiency of the b subunit for factor XIII in the first known case of this condition. The patient is a compound heterozygote of two genetic defects: deletion of A-4161 at the acceptor splice junction of intron A, resulting in a loss of the obligatory AG splicing sequence; and, replacement of G-11499 by T in exon VIII, resulting in an amino acid substitution of Cys430 by Phe. To determine how the latter mutation impaired b subunit synthesis, recombinant b subunit bearing the mutation was expressed in BHK cells. The mutant as well as wild-type b subunit was synthesized by the cells. However, the apparent molecular weight of the mutant was slightly higher than those of the wild-type and plasma b subunits under nonreducing conditions, probably because of destruction of a disulfide bond. The mutant b subunit was secreted from the cells much less effectively than the wild type and remained susceptible to endoglycosidase H, indicating that it was not transported from the endoplasmic reticulum to the Golgi apparatus where the processing of oligosaccharides occurs. Immunofluorescence study suggested that the mutant protein was retained in the endoplasmic reticulum. These studies demonstrate that a Cys430-Phe mutation does not prevent the de novo synthesis of the b subunit, but alters the conformation of the mutant protein sufficiently to impair its intracellular transport, resulting in its deficiency in this patient.

• Norman DG, Barlow PN, Baron M, Day AJ, Sim RB, Campbell ID
• Three-dimensional structure of a complement control protein module in solution.
• J Mol Biol. 1991; 219: 717-25

The complement control protein (CCP) modules (also known as short consensus repeats) are defined by a consensus sequence within a stretch of about 60 amino acid residues. These modules have been identified more than 140 times in over 20 proteins, including 12 proteins of the complement system. The solution structure of the 16th CCP module from human complement factor H has been determined by a combination of 2-dimensional nuclear magnetic resonance spectroscopy and restrained simulated annealing. In all, 548 structurally important nuclear Overhauser enhancement cross-peaks were quantified as distance restraints and, together with 41 experimentally measured angle restraints, were incorporated into a simulated annealing protocol to determine a family of closely related structures that satisfied the experimental observations. The CCP structure is shown to be based on a beta-sandwich arrangement; one face made up of three beta-strands hydrogen-bonded to form a triple-stranded region at its centre and the other face formed from two separate beta-strands. Both faces of the molecule contribute highly conserved hydrophobic side-chains to a compact core. The regions between the beta-strands are composed of both well-defined turns and less well-defined loops. Analysis of CCP sequence alignments, in light of the determined structure, reveals a high degree of conservation amongst residues of obvious structural importance, while almost all insertions, deletions or replacements observed in the known sequences are found in the less well-defined loop regions. On the basis of these observations it is postulated that models of other CCP modules that are based on the structure presented here will be accurate. Certain families of CCP modules differ from the consensus in that they contain extra cysteine residues. As a test of structural consensus, the extra disulphide bridges are shown to be easily accommodated within the determined CCP model.

• Ripoche J, Day AJ, Harris TJ, Sim RB
• The complete amino acid sequence of human complement factor H.
• Biochem J. 1988; 249: 593-602

The complete amino acid sequence of the human complement system regulatory protein, factor H, has been derived from sequencing three overlapping cDNA clones. The sequence consists of 1213 amino acids arranged in 20 homologous units, each about 60 amino acids long, and an 18-residue leader sequence. The 60-amino-acid-long repetitive units are homologous with those found in a large number of other complement and non-complement proteins. Two basic C-terminal residues, deduced from the cDNA sequence, are absent from factor H isolated from outdated plasma. A tyrosine/histidine polymorphism was observed within the seventh homologous repeat unit of factor H. This is likely to represent a difference between the two major allelic variants of factor H. The nature of the cDNA clones indicates that there is likely to be an alternative splicing mechanism, resulting in the formation of at least two species of factor H mRNA.

Disease (disease genes where sequence variants are found in this domain)

SwissProt sequences and OMIM curated human diseases associated with missense mutations within the CCP domain.

Protein	Disease
Beta-2-glycoprotein 1 (P02749) (SMART)	OMIM:138700: APOLIPOPROTEIN H; APOH
P-selectin (P16109) (SMART)	OMIM:173610: Platelet alpha/delta storage pool deficiency
Complement C2a fragment (P06681) (SMART)	OMIM:217000: C2 deficiency
Coagulation factor XIII B chain (P05160) (SMART)	OMIM:134580: Factor XIIIB deficiency

Metabolism (metabolic pathways involving proteins which contain this domain)

% proteins involved	KEGG pathway ID	Description
53.44	map04610	Complement and coagulation cascades
13.23	map04640	Hematopoietic cell lineage
12.70	map04514	Cell adhesion molecules (CAMs)
8.99	map04060	Cytokine-cytokine receptor interaction
3.70	map04080	Neuroactive ligand-receptor interaction
2.12	map04662	B cell receptor signaling pathway
1.59	map00350	Tyrosine metabolism
1.06	map00680	Methane metabolism
1.06	map00940	Phenylpropanoid biosynthesis
1.06	map00360	Phenylalanine metabolism
0.53	map04512	ECM-receptor interaction
0.53	map04510	Focal adhesion

This information is based on mapping of SMART genomic protein database to KEGG orthologous groups. Percentage points are related to the number of proteins with CCP domain which could be assigned to a KEGG orthologous group, and not all proteins containing CCP domain. Please note that proteins can be included in multiple pathways, ie. the numbers above will not always add up to 100%.

Structure (3D structures containing this domain)

3D Structures of CCP domains in PDB

PDB code	Title
1c1z	Crystal structure of human beta-2-glycoprotein-i (apolipoprotein-h)
1ckl	N-terminal two domains of human cd46 (membrane cofactor protein, mcp)
1e5g	Solution structure of central cp module pair of a pox virus complement inhibitor
1elv	Crystal structure of the catalytic domain of human complement c1s protease
1g40	Crystal structure of a complement protein that regulates both pathways of complement activation and binds heparan sulfate proteoglycans
1g44	Crystal structure of a complement control protein that regulates both pathways of complement activation and binds heparan sulfate proteoglycans
1ghq	Cr2-c3d complex structure
1gkg	Structure determination and rational mutagenesis reveal binding surface of immune adherence receptor, cr1 (cd35)
1gkn	Structure determination and rational mutagenesis reveal binding surface of immune adherence receptor, cr1 (cd35)
1gpz	The crystal structure of the zymogen catalytic domain of complement protease c1r
1h03	Human cd55 domains 3 & 4
1h04	Human cd55 domains 3 & 4
1h2p	Human cd55 domains 3 & 4
1h2q	Human cd55 domains 3 & 4
1haq	Four models of human factor h determined by solution scattering curve-fitting and homology modelling
1hcc	Three-dimensional structure of a complement control protein module in solution
1hfh	Solution structure of a pair of complement modules by nuclear magnetic resonance
1hfi	Solution structure of a pair of complement modules by nuclear magnetic resonance
1ly2	Crystal structure of unliganded human cd21 scr1-scr2 (complement receptor type 2)
1m11	Structural model of human decay-accelerating factor bound to echovirus 7 from cryo-electron microscopy
1md7	Monomeric structure of the zymogen of complement protease c1r
1md8	Monomeric structure of the active catalytic domain of complement protease c1r
1ntj	Model of rat crry determined by solution scattering, curve fitting and homology modelling
1ntl	Model of mouse crry-ig determined by solution scattering, curve fitting and homology modelling
1nwv	Solution structure of a functionally active component of decay accelerating factor
1ojv	Decay accelerating factor (cd55): the structure of an intact human complement regulator.
1ojw	Decay accelerating factor (cd55): the structure of an intact human complement regulator.
1ojy	Decay accelerating factor (cd55): the structure of an intact human complement regulator.
1ok1	Decay accelerating factor (cd55): the structure of an intact human complement regulator.
1ok2	Decay accelerating factor (cd55): the structure of an intact human complement regulator.
1ok3	Decay accelerating factor (cd55): the structure of an intact human complement regulator.
1ok9	Decay accelerating factor (cd55): the structure of an intact human complement regulator.
1ppq	Nmr structure of 16th module of immune adherence receptor, cr1 (cd35)
1q3x	Crystal structure of the catalytic region of human masp-2
1qub	Crystal structure of the glycosylated five-domain human beta2-glycoprotein i purified from blood plasma
1rid	Vaccinia complement protein in complex with heparin
1srz	Solution structure of the second complement control protein (ccp) module of the gaba(b)r1a receptor, pro-119 trans conformer
1ss2	Solution structure of the second complement control protein (ccp) module of the gaba(b)r1a receptor, pro-119 cis conformer
1uot	Human cd55 domains 3 & 4
1upn	Complex of echovirus type 12 with domains 3 and 4 of its receptor decay accelerating factor (cd55) by cryo electron microscopy at 16 a
1vvc	C-terminal half of vaccinia virus complement control protein, nmr, minimized average structure
1vvd	C-terminal half of vaccinia virus complement control protein, nmr, 21 structures
1vve	C-terminal half of vaccinia virus complement control protein, nmr, 21 structures
1w2r	Solution structure of cr2 scr 1-2 by x-ray scattering
1w2s	Solution structure of cr2 scr 1-2 in its complex with c3d by x-ray scattering
1y8e	Vcp:suramin complex
1z92	Structure of interleukin-2 with its alpha receptor
1zjk	Crystal structure of the zymogen catalytic region of human masp-2
2a55	Solution structure of the two n-terminal ccp modules of c4b- binding protein (c4bp) alpha-chain.
2aty	Complement receptor chimaeric conjugate cr2-ig
2b5i	Cytokine receptor complex
2bzm	Solution structure of the primary host recognition region of complement factor h
2c8i	Complex of echovirus type 12 with domains 1, 2, 3 and 4 of its receptor decay accelerating factor (cd55) by cryo electron microscopy at 16 a
2ehf	Solution structure of the third sushi domain from human cub and sushi domain-containing protein 1
2erj	Crystal structure of the heterotrimeric interleukin-2 receptor in complex with interleukin-2
2ers	Solution structure of the interleukin-15 receptor sushi domain
2g7i	Structure of human complement factor h carboxyl terminal domains 19-20: a basis for atypical hemolytic uremic syndrome
2gsx	Complement receptor type 2
2ic4	Solution structure of the his402 allotype of the factor h scr6-scr7-scr8 fragment
2jgw	Structure of ccp module 7 of complement factor h - the amd at risk varient (402h)
2jgx	Structure of ccp module 7 of complement factor h - the amd not at risk varient (402y)
2kms	Combined high- and low-resolution techniques reveal compact structure in central portion of factor h despite long inter-modular linkers
2o39	Human adenovirus type 11 knob in complex with domains scr1 and scr2 of cd46 (membrane cofactor protein, mcp)
2ok5	Human complement factor b
2psm	Crystal structure of interleukin 15 in complex with interleukin 15 receptor alpha
2q7z	Solution structure of the 30 scr domains of human complement receptor 1
2qfg	Solution structure of the n-terminal scr-1/5 fragment of complement factor h.
2qfh	Solution structure of the c-terminal scr-16/20 fragment of complement factor h.
2qy0	Active dimeric structure of the catalytic domain of c1r reveals enzyme-product like contacts
2qzd	Fitted structure of scr4 of daf into cryoem density
2qzf	Scr1 of daf from 1ojv fitted into cryoem density
2qzh	Scr2/3 of daf from the nmr structure 1nwv fitted into a cryoem reconstruction of cvb3-rd complexed with daf
2rlp	Nmr structure of ccp modules 1-2 of complement factor h
2rlq	Nmr structure of ccp modules 2-3 of complement factor h
2uwn	Crystal structure of human complement factor h, scr domains 6-8 (h402 risk variant), in complex with ligand.
2v8e	Crystal structure of human complement factor h, scr domains 6-8 (h402 risk variant), in complex with ligand.
2w80	Structure of a complex between neisseria meningitidis factor h binding protein and ccps 6-7 of human complement factor h
2w81	Structure of a complex between neisseria meningitidis factor h binding protein and ccps 6-7 of human complement factor h
2wii	Complement c3b in complex with factor h domains 1-4
2yra	Solution structure of the zinc finger domains (1-87) from human f-box only protein
2z3q	Crystal structure of the il-15/il-15ra complex
2z3r	Crystal structure of the il-15/il-15ra complex
3erb	The crystal structure of c2b, a fragment of complement component c2 produced during c3-convertase formation
3gau	Solution structure of human complement factor h in 50 mm nacl buffer
3gav	Solution structure of human complement factor h in 137 mm nacl buffer
3gaw	Solution structure of human complement factor h in 250 mm nacl buffer
3gov	Crystal structure of the catalytic region of human masp-1
3hrz	Cobra venom factor (cvf) in complex with human factor b
3hs0	Cobra venom factor (cvf) in complex with human factor b

Links (links to other resources describing this domain)

• PFAM: sushi
• INTERPRO: IPR000436