LIG_Integrin_collagen_1

Integrins are metazoan-specific receptors not present in the other crown group taxa 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 24 human integrins, which resemble the evolutionarily most ancient metazoan integrins, can recognize RGD and RGD-like sequence patterns in their ligands: components of the extracellular matrix (ECM), cell surface proteins of cells or other extracellular signaling proteins. In these integrins, the motif binding site is a deep groove between the α and the β subunits of the integrin, with the bound ligand making contacts with both. However, in evolutionarily newer integrins, an additional domain, called the α-I domain, or the inserted interaction domain, can be found on the α subunit. This domain fills up the canonical RGD binding site, and can bind a different type of motif on its opposing side. Once ligand binding occurs, the α-I undergoes a structural rearrangement, filling up the RGD-binding site and initiating downstream signaling similar to RGD-binding integrins.

α-I domains of four integrins - α1β1, α2β1, α10β1, α11β1 - have been described to bind collagens. While there is ample structural and biochemical data on the direct interactions between the described motif in collagens, and α1β1 and α2β1 integrins, the exact details of collagen binding by α10β1 and α11β1 integrins are much less explored. Currently, there is no direct proof that these integrins recognize the same motifs in the same binding mode; however, their similarities to α1β1 and α2β1 integrins makes this very likely.

So far, the well described proteins harbouring this motif are all collagens, and it is presumed that this motif is highly characteristic of this protein family. This is supported by the notion that, contrary to most linear motifs, this specific integrin binding motif occurs in the ordered structural context of trimeric collagen helices. Well studied instances of these collagen motifs seem to lose their binding capacity when taken out of this structural context [Knight,2000]. However, at least one other non-collagen protein has been described in detail that seems to utilize the same binding mode, the streptococcal collagen-like protein [Humtsoe,2005].

In the collagen instances detailed in this entry, the motif is embedded in the typical collagen PPG repeats, with the middle proline being the central residue. This proline is most often hydroxylated, as is common for prolines in collagens in general. Most of our understanding of this motif comes from binding assays with synthetic peptides. Based on these observations [Carafoli,2013], there are two binding modes: high affinity is interacting with two out of the 3 chains of a collagen trimer, while low affinity is interacting with only one. This motif, at least in the high affinity mode, needs the ordered scaffold of the collagen trimer, but does not need the integrin to be activated prior to binding. In contrast, the low affinity mode requires the integrin to be activated, and the two binding modes have different preferences for residues. Several variations can bind integrin α2β1, including GFOGER, GMOGER, GROGER, GLOGEN, GLOGER, GLOGEA, GFOGEK and GFPGER (with ‘O’ representing the hydroxy-proline) although the affinities towards activated and non-activated integrins vary in a wide range. Met in the -1 position seems to be suboptimal but tolerated, and can bind with high affinity to the activated integrin subunit. If the peptide is ideal, such as GFOGER [Knight,2000], then the interaction can form even without the proline hydroxylation; however, proline hydroxylation seems to enhance the binding.