The Eukaryote Linear Motif resource for Functional Sites in Proteins
Accession:
Functional site class:
Integrin binding sites
Functional site description:
Integrins are cell surface receptors responsible for cell migration, cell to extracellular matrix adhesion, and cell to cell adhesion. Integrins are composed of one alpha and one beta subunits. NGR motif is an inactive precursor in fibronectin and fibrillin-1 that undergoes deamidation and forms active isoDGR motif capable of binding RGD-binding pocket of several integrins including alphaVbeta3 and alpha5beta1 integrins. Binding of isoDGR motif to RGD-binding site in integrins inhibits endothelial cells adhesion (Curnis,2006). RGD-binding site is a composite binding site in integrins made of alpha and beta subunits. Integrins are used by viruses to gain entry into the host. Example is adeno-associated type II virus which binds to integrin alpha5beta1 via NGR motif to gain viral entry into the host cell (Asokan,2006). NGR motif-containing peptides coupled to certain drugs are specific against CD13-positive tumour angiogenic vessels.
ELMs with same func. site: LIG_IBS_1  LIG_Integrin_isoDGR_1  LIG_RGD 
ELM Description:
This motif can be found in proteins of the extracellular matrix and it is recognized by different members of the integrin family. The structure of the tenth type III module of fibronectin has shown that the RGD motif lies on a flexible loop.
Pattern: RGD
Pattern Probability: 0.0002366
Present in taxon: Metazoa
Interaction Domains:
o See 21 Instances for LIG_RGD
o Abstract
Integrins are transmembrane receptors responsible primarily for cell migration and extracellular matrix adhesion. Integrins are heterodimers, composed of one alpha, and one beta subunit. They function through bidirectional signalling. There are 18 alpha and 8 beta subunits in the integrin family that assemble into 24 heterodimers. alpha subunits determine integrin ligand specificity whereas beta subunits are connected to the cytoskeleton. alpha and beta subunits are held by non-covalent interactions. Integrins are able to bind a variety of ligands including cell surface adhesion proteins and extracellular matrix proteins. Integrin signalling involves assembly of receptor-ligand complexes on extracellular side of plasma membrane. Integrin proteins are present only in metazoa with no integrins found in fungi, plants, or prokaryotes. The structure of integrin includes extracellular domain which contains ligand binging sites, plasma membrane regions, and short cytoplasmic domains (Barczyk,2009, Campbell,2011).
A hallmark of integrins is the ability of individual family members to recognize multiple ligands. Most integrins recognize relatively short peptide motifs such as RGD, LDV, DLXXL, NGR and, in general, a key constituent residue is an acidic amino acid. Some collagens have another - different - integrin binding motif. The ligand specificities rely on both subunits of a given α-β heterodimer. Proteins that contain RGD motifs recognise 8 out of 24 integrins. RGD was originally identified as the sequence in fibronectin that engages the fibronectin receptor, integrin α5β1. RGD sequences have also been found to be responsible for the cell adhesive properties of a number of other proteins, including fibrinogen, victronectin, von Willebrand factor and many other glycoproteins. Many snake venoms are rich in RGD peptides - a testament to the importance of the integrin system. While their motifs may be more benign, the pharmaceutical industry also finds the integrin-RGD system to be of considerable interest. Antagonists could be effective for therapeutic intervention in cancer, thrombosis and numerous inflammatory conditions.
The IsoDGR motif of integrin-binding ligands arises from the NGR motif via deamidation of asparagine (N) or from the DGR motif via isomerisation of aspartic acid (D). Deamidation is a non-enzymatic reaction that involves the formation of succinimide intermediate and its hydrolysis generating aspartic acid and isoaspartic acid (isoD) residues. The ratio of aspartic acid to isoaspartic acid residues during the deamidation process is 1:3. The D-isoDGR peptide was shown to poorly compete for the RGD binding site. Hence the interaction of isoDGR with integrin is stereospecific favouring L-isomer with L-isoaspartic acid residues being most predominant after deamidation (Curnis,2006, Corti,2011). One of the factors that control the rate of deamidation is the presence of specific amino acids near the asparagine or isoaspartic acid residues. For example glycine near these residues accelerates the process of isoDGR formation (Curnis,2010). Newly formed isoDGR motif mimics a RGD motif and recognises the RGD-binding site of integrins (Corti,2011). One of the proteins that binds to certain integrins via an isoDGR motif is fibronectin (FN). Fibronectins are proteins involved in cell adhesion, motility, shape maintenance, and healing. There are two highly conserved NGR sequences in orthologues of fibronectin. 5th and 7th FN-I repeats each contain a NGR motif that is conserved in human, rat, bird, murine, amphibian, and fish proteins. Both NGR sequences are flanked by glycine residues (GNGRG). IsoDGR motif of fibronectin interacts with integrins by recognition of RGD-binding site of αVβ3, αVβ5, αVβ6, αVβ8, and α5β1 integrins. Integrins such as α1β1, α3β1, α4β7, α5β7, α6β4, and α9β1 cannot be recognised by isoDGR-containing peptides (Curnis,2006). Full-length plasma fibronectin is resistant to asparagine deamidation compared to short fibronectin fragments or peptides containing NGR motif. Hence deamidation of NGR in fibronectin requires proteolytic cleavage. Intracellular enzyme protein-L-isoAsp-O-methyltransferase (PIMT_HUMAN) can inhibit the effects of asparagine deamidation. PIMT converts L-isoaspartic acid and D-aspartic acid to L-aspartic acid residues through methyl-esterification. PIMT can only target extracellular proteins when it is released into extracellular space by damaged vessels and injured tissues. PIMT restores the primary amino acid sequence in case of aspartic acid isomerisation but not in case of asparagine deamidation (Corti,2008, Corti,2011).
NGR and isoDGR motifs might have therapeutic applications that are currently being evaluated. IsoDGR motif-containing peptides are able to recognise αVβ3 integrin-positive endothelial cells in tumour vessels and inhibit tumour growth in tumour-bearing mice as well as inhibit endothelial cells proliferation and adhesion to vitronectin. IsoDGR peptides can be exploited as integrin antagonists for the treatment of cancer and other diseases since isoDGR competes with RGD-containing protein for the RGD-binding pocket (Corti,2011). NGR motif can recognise tumour vasculature by binding to aminopeptidase N (CD13). CD13 is a membrane-bound metalloproteinase that has been implicated in tumour angiogenesis. It is barely expressed by endothelium of normal blood vessels but is significantly upregulated in angiogenic tumour blood vessels. NGR peptide was also shown to target CD13 in inflammation and retinal disorders. Cyclic NGR (NGR flanked by single cysteine on both sides) peptide binds to CD13-positive blood vessels in tumours but not to epithelium of normal kidney or other CD13-rich tissues. First anticancer drug that was coupled to NGR peptide was doxorubicin. It showed reduced toxicity and improved efficacy against human cancer xenografts in nude mice compared to free doxorubicin. NGR peptide has also been coupled to tumour necrosis factor α (TNF-α) that has improved anti-tumour activity. This compound has underwent phase I and phase II trials with 50% of patients treated being stabilised, and having limited toxicity (Corti,2008, Corti,2011).
o 6 selected references:

o 5 GO-Terms:

o 21 Instances for LIG_RGD
(click table headers for sorting; Notes column: =Number of Switches, =Number of Interactions)
Acc., Gene-, NameStartEndSubsequenceLogic#Ev.OrganismNotes
P62384 Disintegrin a
DISG_TRIAB
51 53 KGTICRRARGDDLDDYCNGI TP 1 Trimeresurus gramineus (Indian green tree viper)
1 
P17495 Disintegrin t
DISB_TRIGA
51 53 KGTICRRARGDDLDDYCNGR TP 1 Trimeresurus gramineus (Indian green tree viper)
1 
O43854 EDIL3
EDIL3_HUMAN
96 98 TCEISEAYRGDTFIGYVCKC TP 1 Homo sapiens (Human)
1 
P02887 dscC-1
DIS1B_DICDI
79 81 FMCVALQGRGDHDQWVTSYK TP 1 Dictyostelium discoideum
P13839 Ibsp
SIAL_RAT
289 291 YDENNGEPRGDTYRAYEDEY TP 1 Rattus norvegicus (Norway rat)
P04004 VTN
VTNC_HUMAN
64 66 AECKPQVTRGDVFTMPEDEY TP 1 Homo sapiens (Human)
1 
P29788 Vtn
VTNC_MOUSE
64 66 EQCKPQVTRGDVFTMPEDDY TP 2 Mus musculus (House mouse)
1 
P08721 Spp1
OSTP_RAT
144 146 PTVDVPDGRGDSLAYGLRSK TP 2 Rattus norvegicus (Norway rat)
P04275 VWF
VWF_HUMAN
698 700 PPGLYMDERGDCVPKAQCPC U 0 Homo sapiens (Human)
P11276 Fn1
FINC_MOUSE
1614 1616 ITLYAVTGRGDSPASSKPVS TP 1 Mus musculus (House mouse)
1 
P11276 Fn1
FINC_MOUSE
2181 2183 EVQIGHVPRGDVDYHLYPHV U 0 Mus musculus (House mouse)
P31096 SPP1
OSTP_BOVIN
152 154 PTESANDGRGDSVAYGLKSR TP 1 Bos taurus (Cattle)
P17349 Zinc metallop
VME1_TRIEL
459 461 KRTICRRARGDNPDDRCTGQ TP 1 Protobothrops elegans
1 
P21404 
POLG_CXA9
858 860 TTVAQSRRRGDMSTLNTHGA TP 3 Human coxsackievirus A9 (strain Griggs)
1 
1 
Q66578 
POLG_HPE1H
764 766 KVTSSRALRGDMANLTNQSP TP 1 Echovirus 22 (strain Harris)
1 
1 
P03305 
POLG_FMDVO
869 871 NRNAVPNLRGDLQVLAQKVA TP 1 Foot-and-mouth disease virus (strain O1)
1 
P03276 PIII
CAPSP_ADE02
340 342 EDMNDHAIRGDTFATRAEEK TP 1 Human adenovirus 2
P21815 IBSP
SIAL_HUMAN
286 288 YESENGEPRGDNYRAYEDEY TP 2 Homo sapiens (Human)
P04275 VWF
VWF_HUMAN
2507 2509 CEVVTGSPRGDSQSSWKSVG TP 1 Homo sapiens (Human)
1 
P10451 SPP1
OSTP_HUMAN
159 161 PTVDTYDGRGDSVVYGLRSK TP 2 Homo sapiens (Human)
1 
P02751 FN1
FINC_HUMAN
1524 1526 ITVYAVTGRGDSPASSKPIS TP 3 Homo sapiens (Human)
4 
1 
Please cite: The Eukaryotic Linear Motif Resource ELM: 10 Years and Counting (PMID:24214962)

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