Accession: | |
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Functional site class: | Integrin RGD-type binding sites |
Functional site description: | Integrins are cell adhesion-mediating receptors present in all metazoans. Each integrin is composed of one α and one β subunit; in humans, 18 α and 8 β subunits can combine to form 24 different dimers, each with unique ligand specificities. Eight of the human integrin dimers can recognize ligands with RGD motifs [D'Souza,1991], present in several proteins from humans and pathogens or parasites. The RGD core motif fits into a deep groove between the two subunits with the Arg residue contacting the α subunit and the Asp residue coordinating a divalent cation embedded in the β subunit, held in place by the Metal-Ion-Dependent Adhesion Site (MIDAS) [Xiong,2002], while the flanking residues modify specificity and affinity. The Arg can be replaced by other residues in certain ligands. In addition, an NGR sequence region can naturally degrade into isoDGR (where isoD is an L-Asp residue) through spontaneous deamidation, creating a functional reverse RGD-like binding motif [Curnis,2006]. |
ELMs with same func. site: | LIG_Integrin_isoDGR_2 LIG_Integrin_KxxGD_FGGC_5 LIG_Integrin_RGD_1 LIG_Integrin_RGDSP_6 LIG_Integrin_RGD_TGFB_3 LIG_Integrin_RGDW_4 |
ELM Description: | This variant motif contains the canonical core integrin binding RGD motif followed by a Ser, optionally followed by a Pro. In other subtypes of the RGD motif, the C-terminal flanking residues make additional interactions with the β subunit of the integrin. However, in this subtype, the C-terminal flanking residues minimize such contacts. The RGD core motif is located in a loop-like conformation, and the key Ser is pointing inside the loop, forming a hydrogen bond via its ɣ oxygen with the oxygen of either the Arg (4wk2) or the Gly (4mmx) from the core motif. The optional Pro following the Ser makes minimal contacts with the integrin, and angles the rest of the protein away from the β subunit to further minimize contacts. As a result, proteins bearing this RGD-variant motif can typically interact with a wide range of RGD-binding integrins, showing reduced selectivity. |
Pattern: | RGDSP{0,1} |
Pattern Probability: | 0.0000270 |
Present in taxon: | Metazoa |
Interaction Domains: |
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Abstract |
Integrins are metazoan-specific receptors not present in the other crown group eukaryotes fungi or viridiplantae. All human cells express one or more of the 24 types of dimeric integrins spanning the plasma membrane [Barczyk,2009], which mediate signals between the intracellular space, and neighbouring cells or the extracellular matrix [Takada,2007; Campbell,2011; Hynes,2002]. The presence and ratio of various integrins reflect the cell’s function. Eight of the human integrins (αvβ1, αvβ3, αvβ5, αvβ6, αvβ8, α5β1, α8β1 and αIIbβ3), which resemble the evolutionarily most ancient metazoan integrins, can recognize RGD and RGD-like sequence patterns in their ligands [D'Souza,1991]: components of the extracellular matrix (ECM), cell surface proteins of cells or other extracellular signaling proteins. These interactions are central to regulating tissue integrity and tissue boundary formation [Julich,2015], blood clotting [Hook,2017], angiogenesis [Atkinson,2014] and bone formation [Marie,2014], and regulating nutrient absorption through gastrointestinal motility [Khalifeh-Soltani,2016], amongst other functions. Due to their central roles in cellular communication, misregulation of integrins is implicated in a wide range of diseases. Several viruses, such as the foot-and-mouth disease virus, HIV, West Nile or HPV-16 [Hussein,2015; Asokan,2006] have RGD-like motifs embedded in their proteins that can attach to integrins on the host cell surface, aiding cell entry. Several other pathogens, including both bacteria and eukaryotes also harbour RGD-like motifs to interface with the host cells. Integrins are also known to be targeted by disintegrins [Calvete,2003], a class of proteins present in venoms of snakes from the Viperidae family, ticks, leeches and other parasites. Disintegrins form the strongest known integrin interactions with typical affinities in the low nanomolar - high picomolar range. In addition to pathogenesis, endogenous integrin misregulation is connected to non-pathogenic conditions including Alzheimer’s [Donner,2016], cystic fibrosis [Reed,2015], autism spectrum disorder and schizophrenia [Lilja,2018]. A focal point of therapeutic integrin research is cancer [Seguin,2015], as integrins play pivotal roles in angiogenesis and metastasis. Yet, despite the nearly 80,000 publications on integrins, only a handful of integrin-drugs are available commercially, all targeting RGD-binding integrins. Eptifibatide (an antithrombotic drug), which is a result of semi-rational peptide design, is the only one where the integrin interacting region of a snake venom disintegrin was successfully copied and integrated into a cyclic peptide [Phillips,1997]. Apart from Eptifibatide, such efforts have also produced promising anti-cancer drug candidates, such as Cilengitide and peptides developed to slow down neovasculature formation [Corti,2008]. Other preliminary results show that integrin antagonists could provide a means against inflammatory diseases [Maiguel,2011], HIV infection [Arthos,2018], or could be used in regenerative medicine [Rocha,2018]. One of the reasons for the complexity of integrin regulation is the sensitivity of the downstream signaling to the structural details of ligand binding. While the core RGD motif is common to a wide range of ligands, the exact structural details of the binding determine if the ligand acts as a full or partial agonist or antagonist. There are four major alterations/additions to the presence of the RGD motif that influence this agonistic/antagonistic behaviour, as well as tuning the affinity of the binding and the selectivity profile of the ligand (i. e. which integrin dimers can it bind to): - First, the flanking residues of the core RGD motif, especially the residues following the Asp, have a huge influence on selectivity and binding strength. Certain integrins have multiple binding modes and these flanking residues are able to determine which binding mode a given ligand will use. For example αv αvβ6 and αvβ8 integrins can bind ligands where the RGD and the following sequence region are in coil conformation, such as fibronectin. However, the same integrins can also bind ligands where RGD is followed by a short helix interacting with the β6 or β8 subunit via hydrophobic contacts, such as for TGFβ-1 and -3. The two binding modes require different C-terminal flanking residues and influence the binding strength to the same integrins. - Second, the Arg residue in RGD can be replaced with other residues, most notably Lys, and it can also have a variable position taking advantage of the different side chain length of Lys compared to Arg. Since the interactions formed by Asp itself can be sufficient for biologically relevant binding, the positive charge of RGD can even be omitted in some functional motif instances. - Third, integrins can bind their ligands in an inverted orientation using a reverse motif. In this case, the Asp residue has to be replaced by its mirror image pair, namely L-Asp. Under physiological conditions, Asn residues followed by Gly can spontaneously decay into L-Asp via spontaneous deamidation [Corti,2011; Curnis,2010]. Hence, NGR sequence regions can transform into isoDGR (where isoD represents L-Asp) and they can be actively converted back to NGR by the enzyme protein-L-isoaspartate (D-aspartate) O-methyltransferase (P22061). Natural ligands harbour either an RGD or an NGR motif and some ligands, such as fibronectin, contain both [Curnis,2006]. - Fourth, functional RGD-like motifs often occur in both disordered and ordered regions of proteins. This is in contrast with the notion that most functional short linear motifs reside in disordered protein segments as they need to structurally adapt to their binding partner. However, RGD-like motifs need to adopt a β-turn like conformation to fit into the binding pocket of integrins, and extended surface loops of ordered domains can effectively mimic this conformation. The ordered/disordered nature of an RGD-like motif can heavily influence its binding affinity. As an ordered motif does not lose much conformational entropy upon binding, RGD motifs achieving extremely low Kd values (such as disintegrins [Arruda Macedo,2015]) are most often part of ordered structure, leading to non-transient binding. In contrast, intrinsically flexible ligands such as osteopontin or nephronectin are often disordered to enable a more transient and reversible interaction. |
25 GO-Terms:
6 Instances for LIG_Integrin_RGDSP_6
(click table headers for sorting; Notes column: =Number of Switches, =Number of Interactions)
(click table headers for sorting; Notes column: =Number of Switches, =Number of Interactions)
Acc., Gene-, Name | Start | End | Subsequence | Logic | #Ev. | Organism | Notes |
---|---|---|---|---|---|---|---|
P02751 FN1 FINC_HUMAN |
1615 | 1619 | YVVSVYAQNPSGESQPLVQT | TP | 5 | Homo sapiens (Human) | |
P10451 SPP1 OSTP_HUMAN |
159 | 162 | PTVDTYDGRGDSVVYGLRSK | TP | 5 | Homo sapiens (Human) | |
P04275 VWF VWF_HUMAN |
2507 | 2510 | CEVVTGSPRGDSQSSWKSVG | TP | 1 | Homo sapiens (Human) | |
P03308 Genome polyprotein POLG_FMDVA |
869 | 872 | YSASGSGVRGDSGSLAPRVA | TP | 1 | Foot-and-mouth disease virus (strain A12) | |
Q13201 MMRN1 MMRN1_HUMAN |
186 | 189 | APRETYLSRGDSSSSQRTDY | TP | 2 | Homo sapiens (Human) | |
P04070 PROC PROC_HUMAN |
220 | 224 | IDGKMTRRGDSPWQVVLLDS | TP | 1 | Homo sapiens (Human) |
Please cite:
The Eukaryotic Linear Motif resource: 2022 release.
(PMID:34718738)
ELM data can be downloaded & distributed for non-commercial use according to the ELM Software License Agreement
ELM data can be downloaded & distributed for non-commercial use according to the ELM Software License Agreement