This is the extracellular link domain of the type found in human TSG-6. The link domain is a hyaluronan (HA)-binding domain. TSG-6 is the protein product of tumor necrosis factor-stimulated gene-6. TSG-6 is up-regulated in inflammatory lesions and in the ovary during ovulation. It has a strong anti-inflammatory and chondroprotective effect in models of acute inflammation and autoimmune arthritis and plays an essential role in female fertility. Also included in this group are the stabilins: stabilin-1 (FEEL-1, CLEVER-1) and stabilin-2 (FEEL-2). Stabilin-2 functions as the major liver and lymph node-scavenging receptor for HA and related glycosaminoglycans. Stabilin-2 is a scavenger receptor with a broad range of ligands including advanced glycation end (AGE) products, acetylated low density lipoprotein and procollagen peptides. In contrast, stabilin-1 does not bind HA, but binds acetylated low density lipoprotein and AGEs with lower affinity. As AGEs accumulate in vascular tissues during aging and diabetes, these receptors may be implicated in the pathologies of these states. Both stabilins are present in the early endocytic pathway in hepatic sinusoidal epithelium associating with clathrin/AP-2. Stabilin-1 is expressed in macrophages. Stabilin-2 is absent from the latter. In macrophages: stabilin-1 is involved in trafficking between early/sorting endosomes and the trans-Golgi network. Stabilin-1 has also been implicated in angiogenesis and possibly leucocyte trafficking. Both stabilins bind gram-positive and gram-negative bacteria. TSG-6 and stabilins contain a single link module which supports high affinity binding to HA.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1215489129  83 GVYHRESRSGKYQLTYAEAKAVCEYEGGHLATYQQLEAARKIGFHVCAAGWMAKGRVGYPIVKAGANCGFGRTGIVDYGF 162
Cdd:cd03515     1 GVFHLRSRSGKYKLTYTEAKAACEAEGAHLATYSQLSAAQQLGFHLCAAGWLAKGRVGYPIVFPSANCGFGHVGIVDYGP 80

                          90
                  ....*....|...
gi 1215489129 163 RLNRSERWDAYCY 175
Cdd:cd03515    81 RLNLSERWDAYCY 93

This is the extracellular link domain of the type found in human TSG-6. The link domain is a hyaluronan (HA)-binding domain. TSG-6 is the protein product of tumor necrosis factor-stimulated gene-6. TSG-6 is up-regulated in inflammatory lesions and in the ovary during ovulation. It has a strong anti-inflammatory and chondroprotective effect in models of acute inflammation and autoimmune arthritis and plays an essential role in female fertility. Also included in this group are the stabilins: stabilin-1 (FEEL-1, CLEVER-1) and stabilin-2 (FEEL-2). Stabilin-2 functions as the major liver and lymph node-scavenging receptor for HA and related glycosaminoglycans. Stabilin-2 is a scavenger receptor with a broad range of ligands including advanced glycation end (AGE) products, acetylated low density lipoprotein and procollagen peptides. In contrast, stabilin-1 does not bind HA, but binds acetylated low density lipoprotein and AGEs with lower affinity. As AGEs accumulate in vascular tissues during aging and diabetes, these receptors may be implicated in the pathologies of these states. Both stabilins are present in the early endocytic pathway in hepatic sinusoidal epithelium associating with clathrin/AP-2. Stabilin-1 is expressed in macrophages. Stabilin-2 is absent from the latter. In macrophages: stabilin-1 is involved in trafficking between early/sorting endosomes and the trans-Golgi network. Stabilin-1 has also been implicated in angiogenesis and possibly leucocyte trafficking. Both stabilins bind gram-positive and gram-negative bacteria. TSG-6 and stabilins contain a single link module which supports high affinity binding to HA.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1215489129  83 GVYHRESRSGKYQLTYAEAKAVCEYEGGHLATYQQLEAARKIGFHVCAAGWMAKGRVGYPIVKAGANCGFGRTGIVDYGF 162
Cdd:cd03515     1 GVFHLRSRSGKYKLTYTEAKAACEAEGAHLATYSQLSAAQQLGFHLCAAGWLAKGRVGYPIVFPSANCGFGHVGIVDYGP 80

                          90
                  ....*....|...
gi 1215489129 163 RLNRSERWDAYCY 175
Cdd:cd03515    81 RLNLSERWDAYCY 93

Link (Hyaluronan-binding);

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1215489129   82 AGVYHRESRsGKYQLTYAEAKAVCEYEGGHLATYQQLEAARKIGFHVCAAGWMAKGRVGYPIVKAGANCGFGRTGIVDYG 161
Cdd:smart00445   2 GGVFHVEKN-GRYKLTFAEAREACRAQGATLATVGQLYAAWQDGFDTCDAGWLADGSVRYPIITPRPRCGGNLPGVRQYG 80

                           90
                   ....*....|....*
gi 1215489129  162 FRLNRSeRWDAYCYN 176
Cdd:smart00445  81 FPDPTS-RYDAYCFN 94

CUB domain; extracellular domain; present in proteins mostly known to be involved in development; not found in prokaryotes, plants and yeast.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1215489129 193 FLEFDVEDDTACMADYLEIYDSYDDISGFVGRFCGDELPDDIISTGNVMTLKFLSDASVTAGGFQIRYVT 262
Cdd:cd00041    44 FEDFDLESSPNCSYDYLEIYDGPSTSSPLLGRFCGSTLPPPIISSGNSLTVRFRSDSSVTGRGFKATYSA 113

This is the extracellular link domain of the type found in human TSG-6. The link domain is a hyaluronan (HA)-binding domain. TSG-6 is the protein product of tumor necrosis factor-stimulated gene-6. TSG-6 is up-regulated in inflammatory lesions and in the ovary during ovulation. It has a strong anti-inflammatory and chondroprotective effect in models of acute inflammation and autoimmune arthritis and plays an essential role in female fertility. Also included in this group are the stabilins: stabilin-1 (FEEL-1, CLEVER-1) and stabilin-2 (FEEL-2). Stabilin-2 functions as the major liver and lymph node-scavenging receptor for HA and related glycosaminoglycans. Stabilin-2 is a scavenger receptor with a broad range of ligands including advanced glycation end (AGE) products, acetylated low density lipoprotein and procollagen peptides. In contrast, stabilin-1 does not bind HA, but binds acetylated low density lipoprotein and AGEs with lower affinity. As AGEs accumulate in vascular tissues during aging and diabetes, these receptors may be implicated in the pathologies of these states. Both stabilins are present in the early endocytic pathway in hepatic sinusoidal epithelium associating with clathrin/AP-2. Stabilin-1 is expressed in macrophages. Stabilin-2 is absent from the latter. In macrophages: stabilin-1 is involved in trafficking between early/sorting endosomes and the trans-Golgi network. Stabilin-1 has also been implicated in angiogenesis and possibly leucocyte trafficking. Both stabilins bind gram-positive and gram-negative bacteria. TSG-6 and stabilins contain a single link module which supports high affinity binding to HA.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1215489129  83 GVYHRESRSGKYQLTYAEAKAVCEYEGGHLATYQQLEAARKIGFHVCAAGWMAKGRVGYPIVKAGANCGFGRTGIVDYGF 162
Cdd:cd03515     1 GVFHLRSRSGKYKLTYTEAKAACEAEGAHLATYSQLSAAQQLGFHLCAAGWLAKGRVGYPIVFPSANCGFGHVGIVDYGP 80

                          90
                  ....*....|...
gi 1215489129 163 RLNRSERWDAYCY 175
Cdd:cd03515    81 RLNLSERWDAYCY 93

Extracellular link domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1215489129  83 GVYHRESRsGKYQLTYAEAKAVCEYEGGHLATYQQLEAARKIGFHVCAAGWMAKGRVGYPIVKAGANCGFGRTGIVDYGF 162
Cdd:pfam00193   1 GVFHLESP-GRYKLTFQEAQAACAALGATLATPEQLYAAWKAGLDTCDAGWLADGTVRYPITTPRPNCGGNMPGVRQYGF 79

                          90
                  ....*....|...
gi 1215489129 163 RLNRSERWDAYCY 175
Cdd:pfam00193  80 RDPLSERYDAYCY 92

CUB domain;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1215489129 193 FLEFDVEDDTACMADYLEIYDSYDDISGFVGRFCGDELPDDIISTGNVMTLKFLSDASVTAGGFQIRY 260
Cdd:pfam00431  43 FQDFELEDHDECGYDYVEIRDGPSASSPLLGRFCGSGIPEDIVSSSNQMTIKFVSDASVQKRGFKATY 110

Domain first found in C1r, C1s, uEGF, and bone morphogenetic protein; This domain is found mostly among developmentally-regulated proteins. Spermadhesins contain only this domain.

                           10        20        30        40        50        60        70
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1215489129  189 GSKI---FLEFDVEDDTACMADYLEIYDSYDDISGFVGRFCGDELPDDIIST-GNVMTLKFLSDASVTAGGFQIRY 260
Cdd:smart00042  27 GYRIelqFTDFDLESSDNCEYDYVEIYDGPSASSPLLGRFCGSEAPPPVISSsSNSLTLTFVSDSSVQKRGFSARY 102

This domain is a hyaluronan (HA)-binding domain. It is found in CD44 receptor and mediates adhesive interactions during inflammatory leukocyte homing and tumor metastasis. It also plays an important role in arteriogenesis. The functional HA-binding domain of CD44 is an extended domain comprised of a single link module flanked with N-and C- extensions. These extensions are essential for folding and for functional activity. This group also contains the cell surface retention sequence (CRS) binding protein-1 (CRSBP-1) and lymph vessel endothelial receptor-1 (LYVE-1). CRSBP-1 is a cell surface binding protein for the CRS motif of PDGF-BB (platelet-derived growth factor-BB) and is responsible for the cell surface retention of PDGF-BB in SSV-transformed cells. CRSBP-1 may play a role in autocrine regulation of cell growth mediated by CRS containing growth regulators. LYVE-1 is preferentially expressed on the lymphatic endothelium and is used as a molecular marker for the detection and characterization of lymphatic vessels in tumors.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1215489129  78 TERAAGVYHREsRSGKYQLTYAEAKAVCEYEGGHLATYQQLEAARKIGFHVCAAGWMAKGRVGYPIVKAGANCGFGRTGI 157
Cdd:cd03516     2 TCRIMGVFLVE-KNGRYSLNFTEAKEACRALGLTLASKAQVETALKFGFETCRYGWVEDGFVVIPRIDPNPLCGKNGTGV 80

                          90
                  ....*....|....*....
gi 1215489129 158 vdYGFRLNRSERWDAYCYN 176
Cdd:cd03516    81 --YILNSNLSSRYDAYCYN 97

Link_domain_CSPGs_modules_1_3; this extracellular link domain is found in the first and third link modules of the chondroitin sulfate proteoglycan core protein (CSPG) aggrecan. In addition, it is found in the first link module of three other CSPGs: versican, neurocan, and brevican. The link domain is a hyaluronan (HA)-binding domain. CSPGs are characterized by an N-terminal globular domain (G1 domain) containing two contiguous link modules (modules 1 and 2). Both link modules of the G1 domain of aggrecan are involved in interaction with HA. In addition, aggrecan contains a second globular domain (G2) which contains link modules 3 and 4. G2 appears to lack HA-binding activity. In cartilage, aggrecan forms cartilage link protein stabilized aggregates with HA. These aggregates contribute to the tissue's load bearing properties. Aggregates having other CSPGs substituting for aggrecan may contribute to the structural integrity of many different tissues. Members of the vertebrate HPLN (hyaluronan/HA and proteoglycan binding link) protein family are physically linked adjacent to CSPG genes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1215489129  84 VYHRESRSGKYQLTYAEAKAVCEYEGGHLATYQQLEAARKIGFHVCAAGWMAKGRVGYPIVKAGANCGFGRT---GIVDY 160
Cdd:cd03517     2 VFHYRDATARYALTFPRAQRACLDISAQIATPEQLLAAYEDGFEQCDAGWLADQTVRYPIQTPREGCYGDMDgfpGVRNY 81

                          90
                  ....*....|....*
gi 1215489129 161 GFRlNRSERWDAYCY 175
Cdd:cd03517    82 GVR-DPDELYDVYCY 95

Link_domain_KIAA0527_like; this domain is found in the human protein KIAA0527. Sequence-wise, it is highly similar to the link domain. The link domain is a hyaluronan-binding (HA) domain. KIAA0527 contains a single link module. The KIAA0527 gene was originally cloned from human brain tissue.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 1215489129  88 ESRSGKYQLTYAEAKAVCEYEGGHLATYQQLE-AARKIGFHVCAAGWMAKGRVG 140
Cdd:cd03521     6 ELENGSQGLGLRAARQSCASLGARLASAAELRrAVVECFFSACARGWLADGTVG 59