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25  structures 233  species 0  interactions 18854  sequences 787  architectures

Family: TSP_1 (PF00090)

Summary: Thrombospondin type 1 domain

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

Thrombospondin Edit Wikipedia article

Thrombospondin type 1 domain
PDB 1lsl EBI.jpg
Thrombospondin-1
Identifiers
Symbol TSP_1
Pfam PF00090
InterPro IPR000884
SMART SM00209
PROSITE PS50092
SCOP 1lsl
SUPERFAMILY 1lsl

Thrombospondins (TSP) are secreted proteins with antiangiogenic abilities. TSP was discovered by Nancy L. Baenziger.[1]

Types[edit]

The thrombospondins (TSP) are a family of multifunctional proteins. The family consists of thrombospondins 1-5 and can be divided into 2 subgroups: A, which contains TSP-1 and -2, and B, which contains TSP-3, -4 and -5 (also designated cartilage oligomeric protein or COMP). TSP-1 and -2 are homotrimers, consisting of three identical subunits, whereas TSP-3, -4 and -5 are homopentamers.

TSP-1 and TSP-2 are produced by immature astrocytes during brain development, which promotes the development of new synapses.[2]

Thrombospondin 1[edit]

Thrombospondin 1 (TSP-1) is encoded by THBS1. It was first isolated from platelets that had been stimulated with thrombin, and so was designated 'thrombin-sensitive protein'.[1] Since its first recognition, functions for TSP-1 have been found in multiple biological processes including angiogenesis, apoptosis, activation of TGF-beta and Immune regulation. As such, TSP-1 is designated a multifunctional protein.

TSP-1 has multiple receptors, among which CD36, CD47 and integrins are of particular note.

TSP-1 is an antiangiogenic, inhibiting the proliferation and migration of endothelial cells by interactions with CD36 expressed on their surface of these cells. Inhibitory peptides and fragments of TSP1 bind to CD36, leading to the expression of FAS ligand (FasL), which activates its specific, ubiquitous receptor, Fas. This leads to the activation of caspases and apoptosis of the cell. Since tumors overexpressing TSP-1 typically grow slower, exhibit less angiogenesis, and have fewer metastases, TSP1 is an attractive target for cancer treatment. Because TSP1 is extremely large (~120 kDa monomer), not very abundant and exerts multiple actions, its clinical usefulness is questionable. However, small-molecules based on a CD36-binding peptide sequence from TSP1 are being tested. One analog, ABT-510, exhibits potent proapoptotic activity in cultured cells, while clinically it is very well tolerated with therapeutic benefits reported against several malignancies.[3] ABT-510 is being evaluated in phase II clinical trials for the treatment of several types of cancer.[4]

Human proteins containing this domain[edit]

ADAMTS1; ADAMTS10; ADAMTS12; ADAMTS13; ADAMTS14; ADAMTS15; ADAMTS16; ADAMTS17; ADAMTS18; ADAMTS19; ADAMTS2; ADAMTS20; ADAMTS3; ADAMTS4; ADAMTS5; ADAMTS6; ADAMTS7; ADAMTS8; ADAMTS9; ADAMTSL1; ADAMTSL2; ADAMTSL3; ADAMTSL4; ADAMTSL5; BAI1; BAI2; BAI3; C6; C7; C8A; C8B; C9; C9orf8; C9orf94; CFP; CILP; CILP2; CTGF; CYR61; HMCN1; LIBC; NOV; PAPLN; RSPO1; RSPO3; SEMA5A; SEMA5B; SPON1; SPON2; SSPO; THBS1; THBS2; THSD1; THSD3; THSD7A; THSD7B; UNC5A; UNC5B; UNC5C; UNC5D; WISP1; WISP2; WISP3;

References[edit]

  1. ^ a b Baenziger NL, Brodie GN, Majerus PW (January 1971). "A Thrombin-Sensitive Protein of Human Platelet Membranes". Proc. Natl. Acad. Sci. U.S.A. 68 (1): 240–3. doi:10.1073/pnas.68.1.240. PMC 391203. PMID 5276296. 
  2. ^ Christopherson KS, Ullian EM, Stokes CC,Mullowney CE, Hell JW, Agah A, Lawler J, Mosher DF, Bornstein P, Barres BA. (2005). "Thrombospondins are astrocyte-secreted proteins that promote CNS synaptogenesis". Cell 120 (3): 421–33. doi:10.1016/j.cell.2004.12.020. PMID 15707899. 
  3. ^ Haviv F, Bradley MF, Kalvin DM, et al. (April 2005). "Thrombospondin-1 mimetic peptide inhibitors of angiogenesis and tumor growth: design, synthesis, and optimization of pharmacokinetics and biological activities". Journal of Medicinal Chemistry 48 (8): 2838–46. doi:10.1021/jm0401560. PMID 15828822. 
  4. ^ Sorbera LA, Bayes M (2005). "ABT-510: oncolytic angiogenesis inhibitor". Drugs of the future (Prous Science) 30 (11): 1081–6. doi:10.1358/dof.2005.030.11.949588. 

External links[edit]

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

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No Pfam abstract.

Literature references

  1. Bork P; , FEBS Lett 1993;327:125-130.: The modular architecture of a new family of growth regulators related to connective tissue growth factor. PUBMED:7687569 EPMC:7687569


External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR000884

Thrombospondins are multimeric multidomain glycoproteins that function at cell surfaces and in the extracellular matrix milieu. They act as regulators of cell interactions in vertebrates. They are divided into two subfamilies, A and B, according to their overall molecular organisation. The subgroup A proteins TSP-1 and -2 contain an N-terminal domain, a VWFC domain, three TSP1 repeats, three EGF-like domains, TSP3 repeats and a C-terminal domain. They are assembled as trimer. The subgroup B thrombospondins, designated TSP-3, -4, and COMP (cartilage oligomeric matrix protein, also designated TSP-5) are distinct in that they contain unique N-terminal regions, lack the VWFC domain and TSP1 repeats, contain four copies of EGF-like domains, and are assembled as pentamers [PUBMED:11687483]. EGF, TSP3 repeats and the C-terminal domain are thus the hallmark of a thrombospondin.

This repeat was first described in 1986 by Lawler and Hynes [PUBMED:2430973]. It was found in the thrombospondin protein where it is repeated 3 times. Now a number of proteins involved in the complement pathway (properdin, C6, C7, C8A, C8B, C9) [PUBMED:2459396] as well as extracellular matrix protein like mindin, F-spondin [PUBMED:10409509], SCO-spondin and even the circumsporozoite surface protein 2 and TRAP proteins of Plasmodium [PUBMED:10508153, PUBMED:1501644] contain one or more instance of this repeat. It has been involved in cell-cell interaction, inhibition of angiogenesis [PUBMED:10500044] and apoptosis [PUBMED:9135017].

The intron-exon organisation of the properdin gene confirms the hypothesis that the repeat might have evolved by a process involving exon shuffling [PUBMED:1417780]. A study of properdin structure provides some information about the structure of the thrombospondin type I repeat [PUBMED:1868073].

Domain organisation

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

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Alignments

We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the NCBI sequence database, and our metagenomics sequence database. More...

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We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.

  Seed
(31)
Full
(18854)
Representative proteomes NCBI
(16743)
Meta
(573)
RP15
(2752)
RP35
(3498)
RP55
(6471)
RP75
(10470)
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  Seed
(31)
Full
(18854)
Representative proteomes NCBI
(16743)
Meta
(573)
RP15
(2752)
RP35
(3498)
RP55
(6471)
RP75
(10470)
Alignment:
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Order:
Sequence:
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We make all of our alignments available in Stockholm format. You can download them here as raw, plain text files or as gzip-compressed files.

  Seed
(31)
Full
(18854)
Representative proteomes NCBI
(16743)
Meta
(573)
RP15
(2752)
RP35
(3498)
RP55
(6471)
RP75
(10470)
Raw Stockholm Download   Download   Download   Download   Download   Download   Download   Download  
Gzipped Download   Download   Download   Download   Download   Download   Download   Download  

You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

External links

MyHits provides a collection of tools to handle multiple sequence alignments. For example, one can refine a seed alignment (sequence addition or removal, re-alignment or manual edition) and then search databases for remote homologs using HMMER3.

Pfam alignments:

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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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Seed source: Published_alignment
Previous IDs: tsp_1;
Type: Family
Author: Sonnhammer ELL
Number in seed: 31
Number in full: 18854
Average length of the domain: 50.30 aa
Average identity of full alignment: 28 %
Average coverage of the sequence by the domain: 19.16 %

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 21.6 12.0
Trusted cut-off 21.6 12.0
Noise cut-off 21.5 11.9
Model length: 49
Family (HMM) version: 14
Download: download the raw HMM for this family

Species distribution

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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 TSP_1 domain has been found. There are 25 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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