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368  structures 241  species 7  interactions 23751  sequences 763  architectures

Family: Sushi (PF00084)

Summary: Sushi domain (SCR repeat)

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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]

Structure

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]

Types

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]

Etymology

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

Function

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.[6]

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.[7]

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.[8]

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.[9]

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 extravasion, and may also help prevent inappropriate leukocyte aggregation during vascular stasis.[10]

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,[11][12] showing ‘leukocyte mimicry’.[13]

A number of studies have shown increased expression of carbohydrate ligands on metastatic tumor,[14] enhanced E-selectin expression on the surface of endothelial vessels at the site at tumor metastasis,[15] and the capacity of metastatic tumor cells to roll and adhere to endothelial cells, indicating the role of selectins in metastasis.[16] 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.[17][18]

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 chimiokines 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-β 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.

Research

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.[19] 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.[20]

See also

References

  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. ^ 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 2572800. PMID 18579791. 
  7. ^ 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. 
  8. ^ 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. 
  9. ^ 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. 
  10. ^ 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. 
  11. ^ 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 2559865. PMID 18028011. 
  12. ^ St Hill CA (2012). "Interactions between endothelial selectins and cancer cells regulate metastasis". Front. Biosci. 17: 3233–51. PMID 21622232. 
  13. ^ 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. 
  14. ^ 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. 
  15. ^ 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. 
  16. ^ 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. 
  17. ^ 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 122341. PMID 11854515. 
  18. ^ 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. 
  19. ^ In the lab of Robert Sackstein Harvard University
  20. ^ 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)
Identifiers
Symbol Sushi
Pfam PF00084
InterPro IPR000436
SCOP 1hfi
SUPERFAMILY 1hfi
CDD cd00033

Sushi domain is an evolutionary 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 beta-strands hydrogen-bonded to form a triple-stranded region at its centre, and the other face formed from two separate beta-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.

Subfamilies[edit]

Examples[edit]

Human genes encoding proteins containing this domain include:

References[edit]

  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


Internal database links

External database links

This tab holds annotation information from the InterPro database.

InterPro entry 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.

Domain organisation

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Alignments

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  Seed
(66)
Full
(23751)
Representative proteomes NCBI
(20429)
Meta
(36)
RP15
(3225)
RP35
(3866)
RP55
(7035)
RP75
(12142)
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  Seed
(66)
Full
(23751)
Representative proteomes NCBI
(20429)
Meta
(36)
RP15
(3225)
RP35
(3866)
RP55
(7035)
RP75
(12142)
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  Seed
(66)
Full
(23751)
Representative proteomes NCBI
(20429)
Meta
(36)
RP15
(3225)
RP35
(3866)
RP55
(7035)
RP75
(12142)
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Trees

This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.

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Curation and family details

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Curation View help on the curation process

Seed source: Swissprot_feature_table
Previous IDs: sushi;
Type: Domain
Author: Sonnhammer ELL
Number in seed: 66
Number in full: 23751
Average length of the domain: 57.10 aa
Average identity of full alignment: 26 %
Average coverage of the sequence by the domain: 31.65 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -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: 15
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Species distribution

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Interactions

There are 7 interactions for this family. More...

Rhv A2M_comp Trypsin Sushi VWA Sushi_2 Adeno_knob

Structures

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 368 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 seqence.

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