TY - JOUR
T1 - Linking molecular affinity and cellular specificity in cadherin-mediated adhesion
AU - Katsamba, P.
AU - Carroll, K.
AU - Ahlsen, G.
AU - Bahna, F.
AU - Vendome, J.
AU - Posy, S.
AU - Rajebhosale, M.
AU - Price, S.
AU - Jessell, T. M.
AU - Ben-Shaul, A.
AU - Shapiro, L.
AU - Honig, Barry H.
PY - 2009/7/14
Y1 - 2009/7/14
N2 - Many cell - cell adhesive events are mediated by the dimerization of cadherin proteins presented on apposing cell surfaces. Cadherinmediated processes play a central role in the sorting of cells into separate tissues in vivo, but in vitro assays aimed at mimicking this behavior have yielded inconclusive results. In some cases, cells that express different cadherins exhibit homotypic cell sorting, forming separate cell aggregates, whereas in other cases, intermixed aggregates are formed. A third pattern is observed for mixtures of cells expressing either N- or E-cadherin, which form distinct homotypic aggregates that adhere to one another through a heterotypic interface. The molecular basis of cadherin-mediated cell patterning phenomena is poorly understood, in part because the relationship between cellular adhesive specificity and intermolecular binding free energies has not been established. To clarify this issue, we have measured the dimerization affinities of N-cadherin and E-cadherin. These proteins are similar in sequence and structure, yet are able to mediate homotypic cell patterning behavior in a variety of tissues. N-cadherin is found to form homodimers with higher affinity than does E-cadherin and, unexpectedly, the N/Ecadherin heterophilic binding affinity is intermediate in strength between the 2 homophilic affinities. We can account for observed cell aggregation behaviors by using a theoretical framework that establishes a connection between molecular affinities and cell- cell adhesive specificity. Our results illustrate how graded differences between different homophilic and heterophilic cadherin dimerizaton affinities can result in homotypic cell patterning and, more generally, show how proteins that are closely related can, nevertheless, be responsible for highly specific cellular adhesive behavior.
AB - Many cell - cell adhesive events are mediated by the dimerization of cadherin proteins presented on apposing cell surfaces. Cadherinmediated processes play a central role in the sorting of cells into separate tissues in vivo, but in vitro assays aimed at mimicking this behavior have yielded inconclusive results. In some cases, cells that express different cadherins exhibit homotypic cell sorting, forming separate cell aggregates, whereas in other cases, intermixed aggregates are formed. A third pattern is observed for mixtures of cells expressing either N- or E-cadherin, which form distinct homotypic aggregates that adhere to one another through a heterotypic interface. The molecular basis of cadherin-mediated cell patterning phenomena is poorly understood, in part because the relationship between cellular adhesive specificity and intermolecular binding free energies has not been established. To clarify this issue, we have measured the dimerization affinities of N-cadherin and E-cadherin. These proteins are similar in sequence and structure, yet are able to mediate homotypic cell patterning behavior in a variety of tissues. N-cadherin is found to form homodimers with higher affinity than does E-cadherin and, unexpectedly, the N/Ecadherin heterophilic binding affinity is intermediate in strength between the 2 homophilic affinities. We can account for observed cell aggregation behaviors by using a theoretical framework that establishes a connection between molecular affinities and cell- cell adhesive specificity. Our results illustrate how graded differences between different homophilic and heterophilic cadherin dimerizaton affinities can result in homotypic cell patterning and, more generally, show how proteins that are closely related can, nevertheless, be responsible for highly specific cellular adhesive behavior.
KW - Binding affinities
KW - Cadherins
KW - Cell adhesion
KW - Differential adhesion hypothesis
KW - Surface plasmon resonance
UR - http://www.scopus.com/inward/record.url?scp=67650886055&partnerID=8YFLogxK
U2 - 10.1073/pnas.0905349106
DO - 10.1073/pnas.0905349106
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C2 - 19553217
AN - SCOPUS:67650886055
SN - 0027-8424
VL - 106
SP - 11594
EP - 11599
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 28
ER -