CD2AP (CD2 associated protein)

Alias (NCBI)	CMS
	METS1
HGNC (Hugo)	CD2AP
HGNC Alias symb	CMS
LocusID (NCBI)	23607
Atlas_Id	54896
Location	6p12.3  [Link to chromosome band 6p12]
Location_base_pair	Starts at 47477789 and ends at 47627260 bp from pter ( according to GRCh38/hg38-Dec_2013)  [Mapping CD2AP.png]
Local_order	CD2AP gene is surrounded by LOC105375082 on the 5' end and ADGRF2 on the 3' end (NCBI 2017, Aug 2017). Two pseudogenes (LOC100421517 and RPS12P14) overlap with it.
	Chromosomal location of human CD2AP gene, according to NCBI. CD2AP gene is located on Chromosome 6, starting at 47477746 and ending at 47627263. The gene orientation is on the plus strand.

	The longest transcript of CD2AP gene. It is 5412 bases long and consists of eighteen exons (represented as vertical bars) divided by 17 introns (represented as lines). Two short non coding regions at 5' and 3' complete the transcript. The length of each exon is reported (in number of bases).
Description	The human CD2AP gene is located on chromosome 6p12, it is 149.517 bps long and comprises 18 exons (NCBI Gene ID: 23607, 2017)
Transcription	The longest transcript is 5412 bases long, and comprises 18 exons. This transcript codes for the full lenght protein; four short transcripts (less than 700 bases) have been reported, but their functional role is unknown (Ensemble, Aug 2017). Two of these non-coding isoforms retain part of introns.
Pseudogene	None

	Schematic representation of the CD2AP protein. Three SH3 domains occupy the amino terminal region of the protein (aa 1-330), followed by a short proline-rich motif (336-422). The carboxyl-terminal region contains an actin capping protein (CP) binding motif and a coiled-coil region (577-638) (Dikic 2002, Bruck et al. 2006).
Description	CD2AP protein is an adaptor protein composed of several regions with binding functions: three SH3 domains, one proline rich region, four actin binding domains, AP-2 and CP binding motifs and a coiled-coil region. The protein is 639 aminoacids long and has a predicted molecular weight of 71,451 Dalton. The SH3 domains are located at the amino terminus of the protein and mediate complexes formation. Actually, SH3 domains are short modules of 60 amino acids commonly involved in the assembly and regulation of signalling processes by recognizing polyproline motifs, shaped in a left-handed type II helix, on the surface of the target proteins. In particular, CD2AP SH3 domains selectively recognize polyproline regions containing the consensus PXXXPR. One of this motif is contained in the p53 trascription factor, only in one of the two p53 polymorphic variants P72R, and allows the adaptor protein to selectively bind the 72 R variant (Panni et al. 2015). The crystal structure of two of the SH3 domains of CD2AP have been solved, showing that the domains conserve the typical beta-barrel shape, with five beta strands (Moncalian et al.2006; Yao et al. 2007). Two AP-2 binding motif (FXDXFX) overlap with the first and third SH3 domains respectively, while a third motif lies between the second and the third SH3 (Brett et al. 2002). Beyond these domains, the proline rich region (aa 336-422) contains motifs recognized by the SH3 domains of p130Cas, Src, Fyn, Yes and PI3K, all proteins involved in signal transduction (Kirsch et al. 1999, Dikic 2002). The presence of four putative actin binding sites (aa 534-538; 599-603; 610-614; 631-635) was observed in (Kirsch et al. 1999; Dikic 2002) and the direct binding of CD2AP to actin was shown in (Lehtonen et al. 2002), while the in vivo colocalization and co-immunoprecipitation of CD2AP with actin was demonstrated in (Yuan et al. 2002; Gaidos et al. 2007). Instead a CP (actin barbed-end capping protein) binding motif is present at amino acids 486-502 and mediates the binding of CD2AP to CP (which in turn binds to actin) and the resulting inhibition of the protective function of CP on actin filaments (Bruck et al. 2006; Takeda et al. 2010). The Carboxyl-terminal region adopts a coiled-coil conformation that allows the protein to homodimerise or heterodimerise with the homolog Cin85. (Kirsch et al. 1999, Gaidos et al. 2007)
Expression	CD2AP mRNA is ubiquitously expressed in human tissues (Kirsch et al. 1999). In particular, it is strongly expressed in the placenta, colon, kidney, pancreas and thymus, while a lower expression was detected in aorta, skeletal muscle, bladder and uterus (Kirsch et al. 1999).
Localisation	CD2AP protein is localised mainly to the plasma membrane and to the cytosol
	CD2AP Interaction Network. The network was downloaded from the Intact Database (except for some nodes that were manually added) and visualized with Cytoscape (Orchard et al. 2014; Shannon et al. 2003). Both direct interactions and indirect associations of CD2AP are shown.
Function	The presence of binding domains allows CD2AP to control the assembly of multiprotein complexes and to transmit signals involved in different biological processes. The protein was first identified as p130-Cas interactor (and named CMS as "Cas ligand with Multiple SH3") and its colocalization with p130-Cas and F-actin strongly suggested for a function in the regulation of the actin cytoskeleton as an adaptor protein (Kirsch et al. 1999). This role was largely confirmed by subsequent observations: in normal cells, monomeric actin (G actin) polymerises in filaments (F actin) that bind to CD2AP (Gaidos et al. 2007); in podocytes the absence of CD2AP causes a dramatic defect due to the loss of their specialised actin-rich foot processes that operate the filtration in kidney (Shih et al 1999 ; Gaidos et al. 2007). It was further shown that to guarantee stability to the actin polymer, its barbed ends are in complex with the actin-capping protein CP that avoid the addiction and the loss of monomers. In the presence of CD2AP, CP is prevented to bind actin filaments barbed end, and actin filaments can be extended or shortened (Bruck et al. 2006). Notably, CD2AP is required to recruit CP to the cell periphery during lamellipodia formation (Zhao et al. 2013) and to regulate actin accumulation at the adherens junctions (Tang and Brieher 2013). An independent work identified mouse CD2AP as CD2 receptor clustering activator in the specialized junctions between T cells and antigen-presenting cells (Dustin et al. 1998). This interaction also connects surface receptors to the actin cytoscheleton. A similar model was proposed in Drosophila, where Cindr, the CD2AP homolog, was shown to link cell-cell adhesion junctions with actin cytoscheleton by binding to E-Cadherin and IgCAM Roughest (Johnson et al. 2008; Johnson et al. 2012). It was also observed that upon EGF treatment CBL associates to CD2AP that recruits it to membrane ruffles where they both colocalize (Kirsch et al. 2001; Lynch et al. 2003), linking endocytosis to actin polymerization. RAC1 was found in membrane ruffles in complex with CTTN (cortactin) and CD2AP (Van Dujin et al. 2011). Recently it was suggested that the adaptor protein may anchor a fraction of the 72R variant of the TP53 protein in the cytosol, connecting it with membrane receptors and actin cytoscheleton (Panni et al. 2015). All these observations suggest for a role of CD2AP in regulating membrane proteins and specialized cell junctions and to connect them with actin cytoscheleton dynamics.
	The sequence alignment of the two homolog human proteins CD2AP and Cin85. The SH3 domains are highlighted in yellow and the proline-rich in green. Pink letters indicate the CP binding motif and the Coiled-Coil region. AP2 binding motifs are underlined and positions annotated as potential missense or nonsense mutations in Cosmic database (Forbes et al. 2017) are represented by red letters.
Homology	CD2AP is a member of the Cin85/CMS family of adaptor proteins which comprises two paralogs: CD2AP (CMS) and Cin85 (Figure 5) . They are conserved among mammalian species, but not in C. elegans and yeast. The D. melanogaster homolog, Cindr, only share 30% of homology with CD2AP (Blast Alignment tool https://blast.ncbi.nlm.nih.gov/Blast.cgi).

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