Homophilic and Heterophilic Interactions of Type II Cadherins Identify Specificity Groups Underlying Cell-Adhesive Behavior

Abstract

SUMMARY Type II cadherins are cell-cell adhesion proteins critical for tissue patterning and neuronal targeting but whose molecular binding code remains poorly understood. Here, we delineate binding preferences for type II cadherin cell-adhesive regions, revealing extensive heterophilic interactions between specific pairs, in addition to homophilic interactions. Three distinct specificity groups emerge from our analysis with members that share highly similar heterophilic binding patterns and favor binding to one another. Structures of adhesive fragments from each specificity group confirm near-identical dimer topology conserved throughout the family, allowing interface residues whose conservation corresponds to specificity preferences to be identified. We show that targeted mutation of these residues converts binding preferences between specificity groups in biophysical and co-culture assays. Our results provide a detailed understanding of the type II cadherin interaction map and a basis for defining their role in tissue patterning and for the emerging importance of their heterophilic interactions in neural connectivity.

DIP/Dpr interactions and the evolutionary design of specificity in protein families

“…We have described the structural and energetic origins of the partition of DIPs and Dprs into orthogonal specificity groups defined by SPR-derived binding affinity measurements. We previously analyzed specificity determinants in type II cadherins 5 , nectins 8 and DIPs and Dprs 11 , primarily through visual inspection of sequences guided by structural data. Here we have adopted a far more extensive and quantitative approach as required by the complexity of the problem we set out to address.…”

“…This is critical to their function in the diversification of neuronal identities and self/non-self-discrimination 1-4 . In other cases, for example the type I and type II classical cadherins which pattern epithelia and other tissue structures, specificity is less strict 5-7 . While classical cadherins also exhibit homophilic binding, in addition they show strong heterophilic binding to other select family members 5-7 .…”

“…In other cases, for example the type I and type II classical cadherins which pattern epithelia and other tissue structures, specificity is less strict 5-7 . While classical cadherins also exhibit homophilic binding, in addition they show strong heterophilic binding to other select family members 5-7 . In another example, the nectin adhesion protein family encodes interactions between members that are mainly heterophilic, contributing to the formation of a checkerboard pattern between two cell types, each expressing a cognate nectin.…”

Homophilic and heterophilic cadherin bond rupture forces in homo- or hetero-cellular systems measured by AFM based SCFS

“…The extracellular domain consists of five extracellular cadherin (EC) repeats. A dimer of EC1-EC5 of one cell interacts with the corresponding cadherin dimer of a neighbouring cell through homophilic or heterophilic interaction (2,3).…”

“…According to the presence or absence of the HAV (His-Ala-Val) cell recognition sequence in the EC1 domain, classical cadherins are classified into type I (E-, N-and others) and type II cadherins (OBand others) (2,3). The most commonly expressed cadherin found in fibroblasts is N-cadherin (cad-2) (12).…”