Please note: this site relies heavily on the use of javascript. Without a javascript-enabled browser, this site will not function correctly. Please enable javascript and reload the page, or switch to a different browser.
18  structures 378  species 0  interactions 2908  sequences 32  architectures

Family: Syndecan (PF01034)

Summary: Syndecan domain

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 "Syndecan". More...

Syndecan Edit Wikipedia article

PDB 1ejq EBI.jpg
Solution structure of the Syndecan-4 whole cytoplasmic domain in the presence of phosphatidylinositol 4,5-bisphosphate.
OPM superfamily535
OPM protein6ith

Syndecans are single transmembrane domain proteins that are thought to act as coreceptors, especially for G protein-coupled receptors. These core proteins carry three to five heparan sulfate and chondroitin sulfate chains, which allow for interaction with a large variety of ligands including fibroblast growth factors, vascular endothelial growth factor, transforming growth factor-beta, fibronectin and antithrombin-1. Interactions between fibronectin and some syndecans can be modulated by the extracellular matrix protein tenascin C.

Family members and Structure

The syndecan protein family has four members. Syndecans 1 and 3 and syndecans 2 and 4, making up separate subfamilies, arose by gene duplication and divergent evolution from a single ancestral gene.[1] The syndecan numbers reflect the order in which the cDNAs for each family member were cloned. All syndecans have an N-terminal signal peptide, an ectodomain, a single hydrophobic transmembrane domain, and a short C-terminal cytoplasmic domain.[2] All syndecans are anchored to plasma membrane via a 24-25 amino acid long hydrophobic transmembrane domain, in contrast to another type of cell surface proteoglycans that attaches to cell membrane using a glycosyl-phosphatidyl-inositol linkage.[3] The most obvious differences between syndecans include (together with differences in distribution) the subclassification of the family depending on the existence of GAG binding sites either at both ends of the ectodomain (syndecan-1 and - 3) or at the distal part only (syndecan-2 and -4) and a relatively long Thr-Ser-Pro-rich area in the middle of syndecan- 3’s ectodomain.[3] The ectodomains show the least amount of amino acid sequence conservation, not more than 10–20%; in contrast, the transmembrane and cytoplasmic domains share approximately 60–70% amino acid sequence identity.[4] The transmembrane domains contain an unusual alanine/glycine sequence motif, while the cytoplasmic domain is essentially composed of two regions of conserved amino acid sequence (C1 and C2), separated by a central variable sequence of amino acids that is distinct for each family member (V).

In mammalian cells, syndecans are expressed by unique genes located on different chromosomes. This is general lack of evidence of alternate splicing in syndecan genes. All members of the syndecan family have 5 exons. The difference in size of the syndecans is credited to the variable length of exon 3, which encodes a spacer domain [1, 14]. In humans, the amino acid length of syndecan 1, 2, 3 and 4 is 310, 201, 346 and 198 respectively. Glycosaminoglycan chains, a member of the heparan sulfate group, are an important component of syndecan and are responsible for a diverse set of syndecan functions. The addition of glycosaminoglycans to syndecan is controlled by a series of post- translation events. The preferential site for the addition of glycosaminoglycans is on a serine residue followed by glycine residue, where the linker is attached for the elongation of the glycosaminoglycans by α-N-acetylglucosaminyltransferase I [1]. The linker is composed of four saccharides, first one being xylose, which is an unusual sugar in a unique place, attached to serine of the protein core and sequentially followed by two galactose and a β-D-glucuronic acid [1, 12].


Syndecans are expressed on the cell surface in a cell-specific manner. For example, in mouse cells and tissues, syndecan 1 is highly expressed in fibroblastic and epithelial cells. It is especially high in keratinocytes whereas low in endothelial and neural cells. These tissues include skin, liver, kidney and lungs. Syndecan 2 is highly expressed in endothelial, neural, and fibroblastic cells, whereas it has low expression levels in epithelial cells. It is specific to tissues such as the liver, endothelia and fibroblasts. Syndecan 3 is highly expressed in neural cells, but has low or undetectable amount in epithelial cells. In tissues, it is specific to the brain and expressed at low levels in liver, kidney, lung and small intestine. Syndecan 4 is highly expressed by epithelial and fibroblastic cells, but has low expression levels in neural and endothelial cells. In tissues, it is preferentially expressed in the liver and lungs [11].


Functionality of syndecan is contributed by glycosaminoglycans which help in the interaction with different extracellular ligands. Depending upon the cellular localization of syndecan, glycosaminoglycans have different structures to accommodate the functional needs of the region. The syndecans are known to form homologous oligomers that may be important for their functions.[5]

Functions of syndecan can be categorized in four ways. First is growth-factor-receptor activation. Glycosaminoglycans attached to the syndecan help binding of the various growth factors for activation of important cellular signaling mechanisms. Growth factors such as FGF2, HGF, EGF, VEGF, neuregulins and others interact with syndecans [1, 2, 8]. For example, at the site of tissue injury, the soluble syndecan-1 ectodomains are cleaved by heparanases, producing heparin-like fragments that activate bFGF [13]. Whereas most growth factors interact with syndecans via heparan sulfate chains, the prosecretory mitogen lacritin requires heparanase to both expose and create a binding site in the N-terminus of syndecan 1.[6][7]

Second is matrix adhesion. Syndecans bind to structural extracellular matrix molecules such as collagens I, III, V, fibronectin, thrombospondin, and tenascin to provide structural support for the adhesion [1, 2].

A third function is cell–cell adhesion. Evidence for syndecan’s role in cell–cell adhesion comes from the human myeloma cell line. These myeloma cells had a deficiency in the ability to adhere to one another in a rotation-mediated aggregation matrix. This deficiency is attributed to the lack of syndecan 1 expression. Syndecan 4 also interacts with integrin proteins for cell–cell adhesion [1, 2, 12].

A final role is in tumor suppression and progression. Syndecans act as tumor inhibitors by preventing cellular proliferation of tumor cell lines. For example, in the epithelial-derived tumor cell line, S115, the syndecan 1 ectodomain suppresses the growth of S115 cells without affecting the growth of normal epithelial cells [7]. However, syndecan 1 expression also has a role in tumor progression in myeloma and other cancers [5, 6, 9, 15]. It associates with intracellular actin cytoskeleton and helps maintain normal epithelium sheet morphology

Protein Domains

The syndecan proteins can contain the following protein domains,

  • A signal sequence;
  • An extracellular domain (ectodomain) of variable length whose sequence is not evolutionary conserved in the various forms of syndecans. The ectodomain contains the sites of attachment of the heparan sulphate glycosaminoglycan side chains;
  • A transmembrane region;
  • A highly conserved cytoplasmic domain of about 30 to 35 residues, which could interact with cytoskeletal proteins.[8][9]

Clinical significance


Syndecan-4 is upregulated in endometriosis and inhibition of syndecan-4 in human endometriotic cells results in a reduction of invasive growth in vitro and changes in matrix metalloproteinase expression.[10]


Syndecan-4 is upregulated in osteoarthritis and inhibition of syndecan-4 reduces cartilage destruction in mouse models of OA.[11]

Metabolic regulation and body composition

The Drosophila homologue dSdc and human SDC4 have been implicated in energy homeostasis.[12]

Multiple Myeloma

Syndecan1 is upregulated in multiple myeloma. High levels of shed syndecan1 in a patient's serum typically is correlated with poor prognosis.

Syndecan 1 is the most studied of all the syndecans in cancer research. Many studies have shown that syndecan 1 plays an important role in cancer progression, and also can be used as cancer biomarker. For example, syndecan 1 expression is higher in the bone marrow of the patients suffering from the multiple myeloma [9]. In one published study, the cells expressing the soluble syndecan 1 ectodomain promoted the growth and metastasis of B-lymphoid tumors more extensively than cells bearing surface syndecan 1 or lacking syndecan 1 expression [16]. Similarly, syndecan 1 expression has been linked with low differentiation in squamous cell carcinoma of the head and neck [15].

Syndecan 1 also has been linked with cancer progression by mediating the effects of growth factors in the cells. For example, syndecan 1 expression is increased in ductal breast carcinomas and is associated with factors of angiogenesis and lymphangiogenesis [5]. Studies from patients suffering from endometrial cancer have shown that these patients have increased syndecan 1 expression, and also that expression of this protein positively regulates the endometrial hyperplasia that can progress to endometrial cancer [6].


  1. ^ Carey, D. J. (1997). "Syndecans: multifunctional cell-surface co-receptors". Biochem. J. 327 (Pt 1): 1–16. doi:10.1042/bj3270001. PMC 1218755. PMID 9355727.
  2. ^ Bernfield M, Kokenyesi R, et al. (1992). "Biology of syndecans: a family of transmembrane heparan sulfate proteoglycans". Annu. Rev. Cell Biol. 8: 365–393. doi:10.1146/annurev.cb.08.110192.002053. PMID 1335744.
  3. ^ a b Klaus Elenius & Markku Jalkanen (1994). "Function of the syndecans - a family of cell surface proteoglycans". Journal of Cell Science. 107: 2975–2982. PMID 7698997.
  4. ^ David, G. (1 August 1993). "Integral membrane heparan sulfate proteoglycans". FASEB J. 7 (11): 1023–1030. doi:10.1096/fasebj.7.11.8370471. PMID 8370471.
  5. ^ Sungmun Choi‡1; Lee, E.; Kwon, S.; Park, H.; Yi, J. Y.; Kim, S.; Han, I.-O.; Yun, Y.; Oh, E.-S.; et al. (2005). "Transmembrane Domain-induced Oligomerization Is Crucial for the Functions of Syndecan-2 and Syndecan-4*". The Journal of Biological Chemistry. 280 (52): 42573–42579. doi:10.1074/jbc.M509238200. PMID 16253987.
  6. ^ Ma P, Beck SL, Raab RW, McKown RL, Coffman GL, Utani A, Chirico WJ, Rapraeger AC, Laurie GW (September 2006). "Heparanase deglycanation of syndecan-1 is required for binding of the epithelial-restricted prosecretory mitogen lacritin". The Journal of Cell Biology. 174 (7): 1097–106. doi:10.1083/jcb.200511134. PMC 1666580. PMID 16982797.
  7. ^ Zhang Y, Wang N, Raab RW, McKown RL, Irwin JA, Kwon I, van Kuppevelt TH, Laurie GW (March 2013). "Targeting of heparanase-modified syndecan-1 by prosecretory mitogen lacritin requires conserved core GAGAL plus heparan and chondroitin sulfate as a novel hybrid binding site that enhances selectivity". The Journal of Biological Chemistry. 288 (17): 12090–101. doi:10.1074/jbc.M112.422717. PMC 3636894. PMID 23504321.
  8. ^ Lee D, Oh ES, Woods A, Couchman JR, Lee W (May 1998). "Solution structure of a syndecan-4 cytoplasmic domain and its interaction with phosphatidylinositol 4,5-bisphosphate". J. Biol. Chem. 273 (21): 13022–9. doi:10.1074/jbc.273.21.13022. PMID 9582338.
  9. ^ Shin J, Lee W, Lee D, Koo BK, Han I, Lim Y, Woods A, Couchman JR, Oh ES (July 2001). "Solution structure of the dimeric cytoplasmic domain of syndecan-4". Biochemistry. 40 (29): 8471–8. doi:10.1021/bi002750r. PMID 11456484.
  10. ^ Chelariu-Raicu, A; Wilke, C; Brand, M; Starzinski-Powitz, A; Kiesel, L; Schüring, AN; Götte, M (2016). "Syndecan-4 expression is upregulated in endometriosis and contributes to an invasive phenotype". Fertility and Sterility. 106 (2): 378–85. doi:10.1016/j.fertnstert.2016.03.032. PMID 27041028.
  11. ^ "SDC4: OA Joint effort" 2009
  12. ^ De Luca, Maria; Yann C. Klimentidis; Krista Casazza; Michelle Moses Chambers; Ruth Cho; Susan T. Harbison; Patricia Jumbo-Lucioni; Shaoyan Zhang; Jeff Leips; Jose R. Fernandez (June 2010). Bergmann, Andreas (ed.). "A Conserved Role for Syndecan Family Members in the Regulation of Whole-Body Energy Metabolism". PLoS ONE. 5 (6): e11286. doi:10.1371/journal.pone.0011286. PMC 2890571. PMID 20585652.

External links

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.

Syndecan domain Provide feedback

Syndecans are transmembrane heparin sulfate proteoglycans which are implicated in the binding of extracellular matrix components and growth factors.

Literature references

  1. Lee D, Oh ES, Woods A, Couchman JR, Lee W; , J Biol Chem 1998;273:13022-13029.: Solution structure of a syndecan-4 cytoplasmic domain and its interaction with phosphatidylinositol 4,5-bisphosphate. PUBMED:9582338 EPMC:9582338

Internal database links

External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR027789

Syndecans are multifunctional transmembrane heparan sulphate bearing cell surface receptors [ PUBMED:23559542 ].

Structurally, these proteins consist of four separate domains:

  • A signal sequence;
  • An extracellular domain (ectodomain) of variable length whose sequence is not evolutionary conserved in the various forms of syndecans. The ectodomain contains the sites of attachment of the heparan sulphate glycosaminoglycan side chains;
  • A transmembrane region;
  • A highly conserved cytoplasmic domain of about 30 to 35 residues, which could interact with cytoskeletal proteins.

This entry represents the syndecans cytoplasmic domain [ PUBMED:9582338 ]. The domain is also found in neurexins, which are neuronal cell surface protein that may be involved in cell recognition and cell adhesion

Domain organisation

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

Loading domain graphics...


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 (reference proteomes) using the family HMM. We also generate alignments using four representative proteomes (RP) sets and the UniProtKB sequence database. More...

View options

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.

Representative proteomes UniProt
Jalview View  View  View  View  View  View  View 
HTML View  View           
PP/heatmap 1 View           

1Cannot generate PP/Heatmap alignments for seeds; no PP data available

Key: ✓ available, x not generated, not available.

Format an alignment

Representative proteomes UniProt

Download options

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.

Representative proteomes UniProt
Raw Stockholm Download   Download   Download   Download   Download   Download   Download  
Gzipped 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.

HMM logo

HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...


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.

Note: You can also download the data file for the tree.

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: Pfam-B_1182 (release 3.0)
Previous IDs: none
Type: Family
Sequence Ontology: SO:0100021
Author: Finn RD , Bateman A
Number in seed: 15
Number in full: 2908
Average length of the domain: 62.80 aa
Average identity of full alignment: 47 %
Average coverage of the sequence by the domain: 8.27 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 57096847 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 26.0 26.0
Trusted cut-off 26.0 26.0
Noise cut-off 25.9 25.9
Model length: 62
Family (HMM) version: 22
Download: download the raw HMM for this family

Species distribution

Sunburst controls


Weight segments by...

Change the size of the sunburst


Colour assignments

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


Align selected sequences to HMM

Generate a FASTA-format file

Clear selection

This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the adjacent tab. More...

Loading sunburst data...

Tree controls


The tree shows the occurrence of this domain across different species. More...


Please note: for large trees this can take some time. While the tree is loading, you can safely switch away from this tab but if you browse away from the family page entirely, the tree will not be loaded.


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 Syndecan domain has been found. There are 18 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.

Loading structure mapping...