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651  structures 407  species 23  interactions 47877  sequences 1548  architectures

Family: Sushi (PF00084)

Summary: Sushi repeat (SCR repeat)

Pfam includes annotations and additional family information from a range of different sources. These sources can be accessed via the tabs below.

This is the Wikipedia entry entitled "Selectin". More...

Selectin Edit Wikipedia article

Crystallographic structure P selectin lectin bound to sugar, shown in sticks.[1]

The selectins (cluster of differentiation 62 or CD62) are a family of cell adhesion molecules (or CAMs). All selectins are single-chain transmembrane glycoproteins that share similar properties to C-type lectins due to a related amino terminus and calcium-dependent binding.[2] Selectins bind to sugar moieties and so are considered to be a type of lectin, cell adhesion proteins that bind sugar polymers.[3]


All three known members of the selectin family (L-, E-, and P-selectin) share a similar cassette structure: an N-terminal, calcium-dependent lectin domain, an epidermal growth factor (EGF)-like domain, a variable number of consensus repeat units (2, 6, and 9 for L-, E-, and P-selectin, respectively), a transmembrane domain (TM) and an intracellular cytoplasmic tail (cyto). The transmembrane and cytoplasmic parts are not conserved across the selectins being responsible for their targeting to different compartments.[4] Though they share common elements, their tissue distribution and binding kinetics are quite different, reflecting their divergent roles in various pathophysiological processes.[5]


There are three subsets of selectins:

L-selectin is the smallest of the vascular selectins, expressed on all granulocytes and monocytes and on most lymphocytes, can be found in most leukocytes. P-selectin, the largest selectin, is stored in α-granules of platelets and in Weibel–Palade bodies of endothelial cells, and is translocated to the cell surface of activated endothelial cells and platelets. E-selectin is not expressed under baseline conditions, except in skin microvessels, but is rapidly induced by inflammatory cytokines.

These three types share a significant degree of sequence homology among themselves (except in the transmembrane and cytoplasmic domains) and between species. Analysis of this homology has revealed that the lectin domain, which binds sugars, is most conserved, suggesting that the three selectins bind similar sugar structures. Interestingly, the cytoplasmic and transmembrane domains are highly conserved between species, but not conserved across the selectins. These parts of the selectin molecules are responsible for their targeting to different compartments: P-selectin to secretory granules, E-selectin to the plasma membrane, and L-selectin to the tips of microfolds on leukocytes.[4]


The name selectin comes from the words "selected" and "lectins," which are a type of carbohydrate-recognizing protein.[6]


Selectins are involved in constitutive lymphocyte homing, and in chronic and acute inflammation processes, including post-ischemic inflammation in muscle, kidney and heart, skin inflammation, atherosclerosis, glomerulonephritis and lupus erythematosus[4] and cancer metastasis.

During an inflammatory response, stimuli such as histamine and thrombin cause endothelial cells to mobilize P-selectin from stores inside the cell to the cell surface. In addition, cytokines such as TNF-alpha stimulate the expression of E-selectin and additional P-selectin a few hours later.

As the leukocyte rolls along the blood vessel wall, the distal lectin-like domain of the selectin binds to certain carbohydrate groups presented on proteins (such as PSGL-1) on the leukocyte, which slows the cell and allows it to leave the blood vessel and enter the site of infection. The low-affinity nature of selectins is what allows the characteristic "rolling" action attributed to leukocytes during the leukocyte adhesion cascade.[2]

Each selectin has a carbohydrate recognition domain that mediates binding to specific glycans on apposing cells. They have remarkably similar protein folds and carbohydrate binding residues,[1] leading to overlap in the glycans to which they bind.

Selectins bind to the sialyl Lewis X (SLex) determinant “NeuAcα2-3Galβ1-4(Fucα1-3)GlcNAc.” However, SLex, per se, does not constitute an effective selectin receptor. Instead, SLex and related sialylated, fucosylated glycans are components of more extensive binding determinants.[7]

The best-characterized ligand for the three selectins is P-selectin glycoprotein ligand-1 (PSGL-1), which is a mucin-type glycoprotein expressed on all white blood cells.

Neutrophils and eosinophils bind to E-selectin. One of the reported ligands for E-selectin is the sialylated Lewis X antigen (SLex). Eosinophils, like neutrophils, use sialylated, protease-resistant structures to bind to E-selectin, although the eosinophil expresses much lower levels of these structures on its surface.[8]

Ligands for P-selectin on eosinophils and neutrophils are similar sialylated, protease-sensitive, endo-beta-galactosidase-resistant structures, clearly different than those reported for E-selectin, and suggest disparate roles for P-selectin and E-selectin during recruitment during inflammatory responses.[9]

Bonding mechanisms

Selectins have hinge domains, allowing them to undergo rapid conformational changes in the nanosecond range between ‘open’ and ‘closed’ conformations. Shear stress on the selectin molecule causes it to favor the ‘open’ conformation.[10]

In leukocyte rolling, the ‘open’ conformation of the selectin allows it to bind to inward sialyl Lewis molecules farther up along the PSGL-1 chain, increasing overall binding affinity—if the selectin-sialyl Lewis bond breaks, it can slide and form new bonds with the other sialyl Lewis molecules down the chain. In the ‘closed’ conformation, however, the selectin is only able to bind to one sialyl Lewis molecule, and thus has greatly reduced binding affinity.

The result of such is that selectins exhibit catch and slip bond behavior—under low shear stresses, their bonding affinities are actually increased by an increase in tensile force applied to the bond because of more selectins preferring the ‘open’ conformation. At high stresses, the binding affinities are still reduced because the selectin-ligand bond is still a normal slip bond. It is thought that this shear stress threshold helps select for the right diameter of blood vessels to initiate leukocyte extravasation, and may also help prevent inappropriate leukocyte aggregation during vascular stasis.[11]

Role in cancer

It is becoming evident that selectin may play a role in inflammation and progression of cancer.[4] Tumor cells exploit the selectin-dependent mechanisms mediating cell tethering and rolling interactions through recognition of carbohydrate ligands on tumor cell to enhance distant organ metastasis,[12][13] showing ‘leukocyte mimicry’.[14]

A number of studies have shown increased expression of carbohydrate ligands on metastatic tumor,[15] enhanced E-selectin expression on the surface of endothelial vessels at the site at tumor metastasis,[16] and the capacity of metastatic tumor cells to roll and adhere to endothelial cells, indicating the role of selectins in metastasis.[17] In addition to E-selectin, the role of P-selectin (expressed on platelets) and L-selectin (on leukocytes) in cancer dissemination has been suggested in the way that they interact with circulating cancer cells at an early stage of metastasis.[18][19]

Organ selectivity

The selectins and selectin ligands determine the organ selectivity of metastasis. Several factors may explain the seed and soil theory or homing of metastasis. In particular, genetic regulation and activation of specific chemokines, cytokines and proteases may direct metastasis to a preferred organ. In fact, the extravasation of circulating tumor cells in the host organ requires successive adhesive interactions between endothelial cells and their ligands or counter-receptors present on the cancer cells. Metastatic cells that show a high propensity to metastasize to certain organs adhere at higher rates to venular endothelial cells isolated from these target sites. Moreover, they invade the target tissue at higher rates and respond better to paracrine growth factors released from the target site.

Typically, the cancer cell/endothelial cell interactions imply first a selectin-mediated initial attachment and rolling of the circulating cancer cells on the endothelium. The rolling cancer cells then become activated by locally released chemokines present at the surface of endothelial cells. This triggers the activation of integrins from the cancer cells allowing their firmer adhesion to members of the Ig-CAM family such as ICAM, initiating the transendothelial migration and extravasation processes.[72]

The appropriate set of endothelial receptors is sometimes not expressed constitutively and the cancer cells have to trigger their expression. In this context, the culture supernatants of cancer cells can trigger the expression of E- selectin by endothelial cells suggesting that cancer cells may release by themselves cytokines such as TNF-α, IL-1β or INF-γ that will directly activate endothelial cells to express E-selectin, P-selectin, ICAM-2 or VCAM. On the other hand, several studies further show that cancer cells may initiate the expression of endothelial adhesion molecules in a more indirect ways.

Since the adhesion of several cancer cells to endothelium requires the presence of endothelial selectins as well as sialyl Lewis carbohydrates on cancer cells, the degree of expression of selectins on the vascular wall and the presence of the appropriate ligand on cancer cells are determinant for their adhesion and extravasation into a specific organ. The differential selectin expression profile on endothelium and the specific interactions of selectins expressed by endothelial cells of potential target organs and their ligands expressed on cancer cells are major determinants that underlie the organ-specific distribution of metastases.


Selectins are involved in projects to treat osteoporosis, a disease that occurs when bone-creating cells called osteoblasts become too scarce. Osteoblasts develop from stem cells, and scientists hope to eventually be able to treat osteoporosis by adding stem cells to a patient’s bone marrow. Researchers have developed a way to use selectins to direct stem cells introduced into the vascular system to the bone marrow.[20] E-selectins are constitutively expressed in the bone marrow, and researchers have shown that tagging stem cells with a certain glycoprotein causes these cells to migrate to the bone marrow. Thus, selectins may someday be essential to a regenerative therapy for osteoporosis.[21]

See also


  1. ^ a b PDB: 1G1R​; Somers WS; Tang J; Shaw GD; Camphausen RT (October 2000). "Insights into the molecular basis of leukocyte tethering and rolling revealed by structures of P- and E-selectin bound to SLe(X) and PSGL-1". Cell. 103 (3): 467–79. doi:10.1016/S0092-8674(00)00138-0. PMID 11081633. 
  2. ^ a b Cotran; Kumar, Collins (1998). Robbins Pathologic Basis of Disease. Philadelphia: W.B Saunders Company. ISBN 0-7216-7335-X. 
  3. ^ Parham, Peter (2005). The immune system (2nd ed.). New York: Garland Science. pp. 244–245. ISBN 0-8153-4093-1. 
  4. ^ a b c d Ley K (June 2003). "The role of selectins in inflammation and disease". Trends Mol Med. 9 (6): 263–8. doi:10.1016/S1471-4914(03)00071-6. PMID 12829015. 
  5. ^ Cheung LS; Raman PS; Balzer EM; Wirtz D; Konstantopoulos K (February 2011). "Biophysics of selectin-ligand interactions in inflammation and cancer". Phys Biol. 8 (1): 015013. doi:10.1088/1478-3975/8/1/015013. PMID 21301059. 
  6. ^ Kappelmayer, János; Nagy, Béla (2017). "The Interaction of Selectins and PSGL-1 as a Key Component in Thrombus Formation and Cancer Progression". BioMed Research International. 2017. doi:10.1155/2017/6138145. ISSN 2314-6133. PMC 5478826Freely accessible. 
  7. ^ Nimrichter L; Burdick MM; Aoki K; Laroy W; Fierro MA; Hudson SA; Von Seggern CE; Cotter RJ; Bochner BS; Tiemeyer M; Konstantopoulos K; Schnaar RL (November 2008). "E-selectin receptors on human leukocytes". Blood. 112 (9): 3744–52. doi:10.1182/blood-2008-04-149641. PMC 2572800Freely accessible. PMID 18579791. 
  8. ^ Bochner BS; Sterbinsky SA; Bickel CA; Werfel S; Wein M; Newman W (January 1994). "Differences between human eosinophils and neutrophils in the function and expression of sialic acid-containing counterligands for E-selectin". J. Immunol. 152 (2): 774–82. PMID 7506734. 
  9. ^ Wein M; Sterbinsky SA; Bickel CA; Schleimer RP; Bochner BS (March 1995). "Comparison of human eosinophil and neutrophil ligands for P-selectin: ligands for P-selectin differ from those for E-selectin". Am. J. Respir. Cell Mol. Biol. 12 (3): 315–9. doi:10.1165/ajrcmb.12.3.7532979. PMID 7532979. 
  10. ^ Thomas, W. "For Catch Bonds, it all hinges on the interdomain region". The Journal of Cell Biology. 174: 911–913 (2006). doi:10.1083/jcb.200609029. PMC 2064382Freely accessible. PMID 17000873. 
  11. ^ Yago, Tadayuki. "Catch Bonds Govern Adhesion through L-selectin at Threshold Shear". The Journal of Cell Biology. 166: 913–923 (2004). doi:10.1083/jcb.200403144. PMC 2172126Freely accessible. PMID 15364963. 
  12. ^ Barthel SR; Gavino JD; Descheny L; Dimitroff CJ (November 2007). "Targeting selectins and selectin ligands in inflammation and cancer". Expert Opin. Ther. Targets. 11 (11): 1473–91. doi:10.1517/14728222.11.11.1473. PMC 2559865Freely accessible. PMID 18028011. 
  13. ^ St Hill CA (2012). "Interactions between endothelial selectins and cancer cells regulate metastasis". Front. Biosci. 16: 3233–51. doi:10.2741/3909. PMID 21622232. 
  14. ^ Witz IP (2006). "Tumor-microenvironment interactions: the selectin-selectin ligand axis in tumor-endothelium cross talk". Cancer Treat. Res. Cancer Treatment and Research. 130: 125–40. doi:10.1007/0-387-26283-0_6. ISBN 978-0-387-26282-6. PMID 16610706. 
  15. ^ Nakamori S; Kameyama M; Imaoka S; Furukawa H; Ishikawa O; Sasaki Y; Izumi Y; Irimura T (April 1997). "Involvement of carbohydrate antigen sialyl Lewis(x) in colorectal cancer metastasis". Dis. Colon Rectum. 40 (4): 420–31. doi:10.1007/BF02258386. PMID 9106690. 
  16. ^ Matsuura N; Narita T; Mitsuoka C; Kimura N; Kannagi R; Imai T; Funahashi H; Takagi H (1997). "Increased concentration of soluble E-selectin in the sera of breast cancer patients". Anticancer Res. 17 (2B): 1367–72. PMID 9137500. 
  17. ^ Gout S; Morin C; Houle F; Huot J (September 2006). "Death receptor-3, a new E-Selectin counter-receptor that confers migration and survival advantages to colon carcinoma cells by triggering p38 and ERK MAPK activation". Cancer Res. 66 (18): 9117–24. doi:10.1158/0008-5472.CAN-05-4605. PMID 16982754. 
  18. ^ Borsig L; Wong R; Hynes RO; Varki NM; Varki A (February 2002). "Synergistic effects of L- and P-selectin in facilitating tumor metastasis can involve non-mucin ligands and implicate leukocytes as enhancers of metastasis". Proc. Natl. Acad. Sci. U.S.A. 99 (4): 2193–8. doi:10.1073/pnas.261704098. PMC 122341Freely accessible. PMID 11854515. 
  19. ^ Peeters CF; Ruers TJ; Westphal JR; de Waal RM (February 2005). "Progressive loss of endothelial P-selectin expression with increasing malignancy in colorectal cancer". Lab. Invest. 85 (2): 248–56. doi:10.1038/labinvest.3700217. PMID 15640834. 
  20. ^ In the lab of Robert Sackstein Harvard University
  21. ^ Sackstein Lab

External links

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

This is the Wikipedia entry entitled "Sushi domain". More...

Sushi domain Edit Wikipedia article

Sushi domain (SCR repeat)
Symbol Sushi
Pfam PF00084
InterPro IPR000436
SCOP 1hfi
CDD cd00033

Sushi domain is an evolutionarily conserved protein domain.

Sushi domains, 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 β-strands hydrogen-bonded to form a triple-stranded region at its centre, and the other face formed from two separate β-strands.[1]

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.[2] 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.



Human genes encoding proteins containing this domain include:


  1. ^ Campbell ID, Baron M, Day AJ, Sim RB, Norman DG, Barlow PN (1991). "Three-dimensional structure of a complement control protein module in solution". J. Mol. Biol. 219 (4): 717–725. doi:10.1016/0022-2836(91)90666-T. PMID 1829116. 
  2. ^ Lomas-Francis, Christine; Reid, Marion E. (2004). The blood group antigen: factsbook. Boston: Academic Press. ISBN 0-12-586585-6. 

This article incorporates text from the public domain Pfam and InterPro IPR000436

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.

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Literature references

  1. Ichinose A, Bottenus RE, Davie EW; , J Biol Chem 1990;265:13411-13414.: Structure of transglutaminases. PUBMED:1974250 EPMC:1974250

  2. Kato H, Enjyoji K; , Biochemistry 1991;30:11687-11694.: Amino acid sequence and location of the disulfide bonds in bovine beta 2 glycoprotein I: the presence of five Sushi domains. PUBMED:1751487 EPMC:1751487

External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR000436

The extracellular sushi domain is characterised by a consensus sequence spanning ~60 residues containing four invariant cysteine residues forming two disulfide-bridges (I-III and II-IV), a highly conserved tryptophan, and conserved glycine, proline, and hydrophobic residues [PUBMED:2751824]. Sushi domains are known to be involved in many recognition processes, including the binding of several complement factors to fragments C3b and C4b [PUBMED:2751824]. The sushi domain is also known as the complement controle protein (CCP) module or the short consensus repeat (SCR).

Several structure of the sushi domain have been solved (see for example {PDB:1HCC}) [PUBMED:1829116]. The sushi domain folds into a small and compact hydrophobic core enveloped by six beta-strands and stabilised by two disulfide bridges. The relative structural orientation of the Beta-2 and Beta-4 strands is shared by all the sushi structures, whereas the topology of the other strands relative to this central conserved core is variable, especially at the regions that form the interfaces with the preceding and following domains [PUBMED:10775260].

Domain organisation

Below is a listing of the unique domain organisations or architectures in which this domain is found. More...

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Pfam Clan

This family is a member of clan EGF (CL0001), which has the following description:

Members of this clan all belong to the EGF superfamily. This particular superfamily is characterised as having least 6 cysteine residues. These cysteines form disulphide bonds, in the order 1-3, 2-4, 5-6, which are essential for the stability of the EGF fold. These disulphide bonds are stacked in a ladder-like arrangement. The Laminin EGF family is distinguished by having an an additional disulphide bond. The function of the domains within this family remains unclear, but they are thought to largely perform a structural role. More often than not, these domains are arranged in tandem repeats in extracellular proteins.

The clan contains the following 21 members:

cEGF CFC DSL EGF EGF_2 EGF_3 EGF_alliinase EGF_CA EGF_MSP1_1 EGF_Tenascin Fibrillin_U_N FOLN FXa_inhibition Gla hEGF I-EGF_1 Laminin_EGF Plasmod_Pvs28 Sushi Sushi_2 Tme5_EGF_like


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Curation and family details

This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.

Curation View help on the curation process

Seed source: Swissprot_feature_table
Previous IDs: sushi;
Type: Domain
Sequence Ontology: SO:0000417
Author: Sonnhammer ELL
Number in seed: 33
Number in full: 47877
Average length of the domain: 56.80 aa
Average identity of full alignment: 26 %
Average coverage of the sequence by the domain: 28.72 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 45638612 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 20.7 17.0
Trusted cut-off 20.7 17.0
Noise cut-off 20.6 16.9
Model length: 56
Family (HMM) version: 20
Download: download the raw HMM for this family

Species distribution

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Colour assignments

Archea Archea Eukaryota Eukaryota
Bacteria Bacteria Other sequences Other sequences
Viruses Viruses Unclassified Unclassified
Viroids Viroids Unclassified sequence Unclassified sequence


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There are 23 interactions for this family. More...

HN Rhv MG2 Adeno_knob VWA TED_complement CUB Sushi_2 NTR OspE A2M_BRD A2M TED_complement IL2 Sushi Trypsin Trypsin Adeno_knob A2M IL2 Lipoprot_C Lipoprot_C IL15


For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the Sushi domain has been found. There are 651 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein sequence.

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