The alleles of PECAM-1
Introduction
PECAM-1 (CD31) is a vascular cell adhesion and signaling receptor that is expressed on the surfaces of platelets, leukocytes, and endothelial cells (Newman et al., 1990), and is encoded by a ∼ 70 kb gene near the end of the long arm of chromosome 17 (17q23) (Gumina et al., 1996). PECAM-1 exists in mature form as a 130 kDa Type I transmembrane glycoprotein comprised of a 574 amino acid extracellular domain containing six Ig-like homology domains, a 19 amino acid transmembrane domain, and a cytoplasmic tail of varying length due to alternative splicing (Kirschbaum et al., 1994). Ig-domain 1 mediates homophilic binding (Liao et al., 1997, Newton et al., 1997, Sun et al., 1996), while Ig-domain 6 binds calcium (Jackson et al., 1997a) and has been suggested to participate in cis interactions with integrin αvβ3 within the plane of the plasma membrane (Wong et al., 2000). The cytoplasmic tail of PECAM-1 possesses two Immunoreceptor Tyrosine Inhibitory Motifs (ITIMs) (Newman, 1999) which, upon tyrosine phosphorylation, recruit and activate the protein tyrosine phosphatase, SHP-2 (Jackson et al., 1997b, Masuda et al., 1997, Sagawa et al., 1997). PECAM-1 has been demonstrated to participate in a variety of physiological events, including leukocyte adhesion and migration, angiogenesis, apoptosis, and modulation of Immunoreceptor Tyrosine Activating Motif (ITAM)-mediated cellular activation (for recent reviews, see (Ilan and Madri, 2003, Newman, 1997, Newman and Newman, 2003)).
Like most genes, variations within the nucleotide sequence of the PECAM-1 gene have been reported, with individual polymorphic residues identified within the 5′UTR, the extracellular and cytoplasmic domains, and the 3′UTR (summarized in Table 1). While the effects of these polymorphisms on PECAM-1-mediated adhesion or signaling have not yet been determined, mismatches at PECAM-1 amino acid residues 98, 536, or 643 have often (Balduini et al., 1999, Behar et al., 1996, Cavanagh et al., 2005, Grumet et al., 2001, Maruya et al., 1998), though not universally (Nichols et al., 1996), been associated with an increased incidence of acute graft-versus-host disease (GVHD), and these and other PECAM-1 polymorphisms have been linked with early onset of atherosclerosis (Elrayess et al., 2003), increased risk of cardiovascular disease (Elrayess et al., 2004, Fang et al., 2005, Listi et al., 2004, Sasaoka et al., 2001, Song et al., 2003, Wei et al., 2004), and susceptibility to malarial infection (Kikuchi et al., 2001), though the latter is also controversial (Casals-Pascual et al., 2001).
While the frequencies of individual PECAM-1 polymorphisms have been determined in a limited number of population studies, these polymorphisms have not, to date, been linked into distinct PECAM-1 alleles, hampering efforts to more definitively establish PECAM-1-related disease associations. The purpose of the present investigation, therefore, was to determine the major alleles bearing each of the most commonly reported SNPs within the PECAM-1 gene. This information should not only permit more precise bio-epidemiological associations to be made amongst different human populations, but also enable biochemical and cell biological studies to be performed to investigate whether functional differences between PECAM-1 allelic isoforms might be causally linked to the reported disease associations of PECAM-1 SNPs.
Section snippets
Preparation of genomic and cDNA from human whole blood
Human whole blood was obtained from anonymous volunteer blood donors. RNA was isolated using a QIAamp® RNA Blood Mini Kit according to manufacturer's instructions (Qiagen, Valencia, CA). cDNA was then prepared from human RNA using the SuperScript™ First-Strand Synthesis for RT-PCR kit (Invitrogen, Carlsbad CA). Following cDNA synthesis, RNase (1 μl) (Invitrogen) was added, tubes incubated at 37 °C for 20 min, and then put on ice or frozen at − 20 °C for later use. Genomic DNA was isolated from
Identification of the primary alleles of human PECAM-1
Single nucleotide polymorphisms within the PECAM-1 gene, including several that result in amino acid substitutions, were originally identified by comparing the sequences of PECAM-1 cDNAs cloned from different laboratories (Newman et al., 1990, Simmons et al., 1990, Stockinger et al., 1990, Zehnder et al., 1992), as well as the single sequence derived thus far from PECAM-1 genomic DNA (Kirschbaum et al., 1994). The frequencies for several individual SNPs have since been determined in several
Acknowledgements
The authors thank Daniel B. Rowe, Ph.D., Division of Biostatistics, Medical College of Wisconsin, for his assistance in statistical analysis. This study was funded by grants HL-40126 and Training Grant HL-07209 from the Heart, Lung, and Blood Institute of the National Institutes of Health grant.
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Structural basis for PECAM-1 homophilic binding
2016, BloodCitation Excerpt :The residues in strands B and E and the C′E loop of IgD1 molecule 1 pack against residues Asn8, Ser9, Asp11, Phe31, Ala32, Asp33, Ser35, Ser63, Thr64 within strands A, B, and E of IgD1 molecule 2 (Figure 4B). Finally, the common L98V polymorphic residue that has been implicated as a risk factor for cardiovascular disease52 is buried well inside the IgD1 structure, and does not contribute to the PECAM-1/PECAM-1 homophilic interface. In all, 16 residues contribute to the 814-Å2 interfacial area of IgD1 molecule 1 (Figure 4D), whereas 18 residues contribute to the 794-Å2 interfacial area of IgD1 molecule 2 (Figure 4F).
PECAM-1
2013, PlateletsPECAM-1
2012, Platelets, Third EditionInvestigation of the effect of donor platelet endothelial cell adhesion molecule 1 polymorphism on the graft-vs.-host disease occurrence in Tunisian recipients of hematopoietic stem cells
2011, Clinical BiochemistryCitation Excerpt :At the genetic level, this signalling receptor is encoded by a single gene of about 70 kb consisting of 16 exons and maps to chromosome 17q23 [14,16,17]. In mature form, PECAM-1 molecule is of 130 kDa containing especially an extracellular domain of 574 amino acids that contains 6 Ig-like C2-type domains [14]. The cytoplasmic domain, which is of 118 amino acids, contains an ITIM motif (immunoreceptor tyrosine-based inhibitory motif) and is serine and tyrosine phosphorylated following cellular activation.
Acute graft-vs.-host disease correlates with the disparity for the PECAM-1 S536N polymorphism only in the HLA-B44-like positive Tunisian recipients of HSCs
2010, Cellular ImmunologyCitation Excerpt :The GVHD reaction, occurring even in HLA-identical HSCT context, has been widely linked to disparity between the recipient and its donor for some MiHAgs which may generate anti-host CTLs and T helper cells with specific activity thereby enhancing the afferent phase of this outcome [3,5–7]. In this paradigm, the PECAM-1 molecule was described as potential candidate human MiHAg relevant to GVHD due to its large tissue distribution and the structure of its extracellular domain [23]. Thus, several studies were conducted in order to examine the effect of disparity for this marker between the recipient and its HLA-identical donor on the occurrence of GVHD and reported data were in disagreement about the significance of this association.