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Structure of the N Terminus of Cadherin 23 Reveals a New Adhesion Mechanism for a Subset of Cadherin Superfamily Members

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Structure of the N Terminus of Cadherin 23 Reveals a New Adhesion Mechanism for a Subset of Cadherin Superfamily Members Structure of the N terminus of cadherin 23 reveals a new adhesion mechanism for a subset of cadherin superfamily members Heather M. Elledgea,b,1, Piotr Kazmierczaka,b,1, Peter Clarka,1, Jeremiah S. Josepha, Anand Kolatkara, Peter Kuhna,2, and Ulrich Müllera,b,2 aDepartment of Cell Biology and bDorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA 92037 Communicated by Kevin P. Campbell, University of Iowa College of Medicine, Iowa City, IA, May 7, 2010 (received for review April 5, 2010) The cadherin superfamily encodes more than 100 receptors with X-dimer because the dimeric assembly of the elongated molecules diverse functions in tissue development and homeostasis. Classical resembles the shape of an X. Residues near the EC1–EC2 Ca2+ cadherins mediate adhesion by binding interactions that depend on binding sites mediate X-dimer formation. Earlier crystallographic their N-terminal extracellular cadherin (EC) domains, which swap N- studies of E-cadherin fragments containing small N-terminal terminal β-strands. Sequence alignments suggest that the strand- extensions revealed a similar X-dimer structure (9, 11), which likely swap binding mode is not commonly used by functionally divergent reflected these binding intermediates. T-cadherin contains the cadherins. Here, we have determined the structure of the EC1–EC2 conserved residues near the EC1–EC2 Ca2+ binding sites but lacks domains of cadherin 23 (CDH23), which binds to protocadherin 15 strand-swapping signatures. Crystallographic studies of EC1–EC2 (PCDH15) to form tip links of mechanosensory hair cells. Unlike clas- of T-cadherin reveal an X-dimer structure, suggesting that this sical cadherins, the CDH23 N terminus contains polar amino acids cadherin interacts by this binding mode alone (6). that bind Ca2+. The N terminus of PCDH15 also contains polar amino We have recently shown that two cadherin superfamily members, acids. Mutations in polar amino acids within EC1 of CDH23 and CDH23 and PCDH15, interact to form tip links, which gate PCDH15 abolish interaction between the two cadherins. PCDH21 mechanotransduction channels in hair cells of the inner ear (15). The and PCDH24 contain similarly charged N termini, suggesting that two cadherins are also expressed in retinal photoreceptors, and NEUROSCIENCE a subset of cadherins share a common interaction mechanism that mutations in their genes lead to deaf-blindness in humans (1, 16). differs from the strand-swap binding mode of classical cadherins. Unlike adhesion complexes between cells, tip links do not contain thousands of cadherin molecules and are instead formed by one hair cell | tip link | hair cell | PCDH21 | PCDH24 CDH23 homodimer interacting in trans with one PCDH15 homo- dimer (15). The EC1 domains of CDH23 and PCDH15 mediate he organization of cells into tissues and organs depends on cad- binding interactions, but CDH23 and PCDH15 lack strand-swapping Therin molecules that regulate such diverse processes as cell ad- signatures, suggesting that they interact by a mechanism different hesion, synapse formation, and the development and function of from classical cadherins. We therefore set out to gain insights into the sensory cells in the inner ear and retina (1–4). The defining feature of structure and binding mechanism of tip-link cadherins. the cadherin superfamily is the extracellular cadherin (EC) domain, which occurs in varying repetitions in all cadherins. Based on se- Results quence homology and domain structure, cadherins are divided into Structure of the N-terminal EC1–EC2 Domains of CDH23 Reveals subfamilies including the classical cadherins, desmosomal cadherins, Unique Features Not Shared with Classical Cadherins. CDH23 from seven transmembrane cadherins, and protocadherins. Classical cad- different species lacks Trp residues that are conserved in classical herins and desmosomal cadherins are the best-studied superfamily cadherins, but contains an N-terminal extension (Fig. 1A), sug- members and have well-documented roles in mediating cell adhesion gesting that CDH23 mediates adhesive interactions by a mecha- and the formation of desmosomes, respectively (1–4). The function nism different from classical cadherins. To test this model, we first and adhesive properties of other cadherin superfamily members are determined the crystal structure of the EC1–EC2 fragment of less well studied. mouse CDH23 at a resolution of 1.1 Å (Fig. 1 B and C and Table S1; Crystallographic and biochemical studies have provided insights PDB ID 3MVS). Numberings in sequences throughout the manu- into the structure of cadherin extracellular domains and the mech- script start with the first amino acid of the mature CDH23 EC1 anism that mediates adhesion between classical cadherins (5–13). domain (Glu1). The EC1–EC2 fragment was expressed in Escher- The EC domain forms a protein module of the Ig-like fold consisting ichia coli with an affinity tag, which was removed before crystalli- of seven β-strands that are arranged as two opposed β-sheets. The N- zation. Analysis by size exclusion chromatography showed that the and C termini reside on opposite ends of the EC domain, facilitating protein fragment behaved as a monomer in solution. EC1 and EC2 the formation of tandem repeats. The connections between succes- domains of CDH23 have 22.8% sequence identity, and our struc- sive EC domains are rigidified by coordination of three Ca2+ ions, tural analyses show that they have characteristic cadherin domain which is mediated by amino acids that are conserved in all cadherins (5,9,14).Adhesionspecificity resides in the EC1 domains. The crystallographic structures show that the adhesive binding interface is Author contributions: H.M.E., P. Kazmierczak, P.C., J.S.J., A.K., and U.M. designed research; “ ” β H.M.E., P. Kazmierczak, P.C., J.S.J., and A.K. performed research; H.M.E., P. Kazmierczak, formed by swapping of the amino-terminal -strands of opposite P.C., J.S.J., A.K., P. Kuhn, and U.M. analyzed data; and P. Kuhn and U.M. wrote the paper. EC1 domains, whereby the strand of one monomer replaces the The authors declare no conflict of interest. strand of the other. Critical for this interaction are the side chains of fi Data deposition: The atomic coordinates and structure factors have been deposited in the conserved Trp residues, which t into hydrophobic pockets on the Protein Data Bank, www.rcsb.org (PDB ID code 3MVS). EC1 domain of the binding partner (5, 8, 10). 1 fi H.M.E., P. Kazmierczak, and P.C. contributed equally to this work. Recent ndings suggest that the formation of cadherin adhesion 2 To whom correspondence may be addressed. E-mail: [email protected] or pkuhn@ complexes is a multistep process, where cadherins establish a so scripps.edu. “ ” called X-dimer intermediate that facilitates the subsequent for- This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. mation of the strand-swapped dimer (7). The intermediate is called 1073/pnas.1006284107/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1006284107 PNAS Early Edition | 1of5 Downloaded by guest on September 29, 2021 CDH23-hu QVNRLPFFTNHFFDTYLLISEDTPVGSSVTQLLARDMDNDPLVFGVSGEEASR----FFA 56 CDH23 EC2-EC3 A CDH23-mu QVNRLPFFTNHFFDTYLLISEDTPVGSSVTQLLARDMDNDPLVFGVSGEEASR----FFA 56 A CDH23-ch QVNRLPYFINHFFDTYLLISEDTPVGTSVTQLLARDMDNDPLVFGVSGEEASR----FFA 56 CDH23-da QVNQPPRFQNYFFQSYLLVYEDTPVGTSITQLQAVDPDGEPLIFGVVGEEAMR----YFA 56 CDH1-mu --------DWVIPPISCPENEKGEFPKNLVQIKSNRDKETKVFYSITGQGADKPPVGVFI 52 CDH2-mu --------DWVIPPINLPENSRGPFPQELVRIRSDRDKNLSLRYSVTGPGADQPPTGIFI 52 .. ..:.:: : .: : :.::* *.: .* CDH23-hu VEPDTGVVWLRQPLDRETKSEFTVEFSVSDHQGVITR---KVNIQVGDVNDNAP 107 CDH23-mu VEPDTGVVWLRQPLDRETKSEFTVEFSVSDHQGVITR---KVNIQVGDVNDNAP 107 CDH23-ch VESDTGVVWLRQPLDRETKSEFTVEFSVSDHQGVITR---KVNIQVGDVNDNAP 107 CDH23 EC1-EC2 CDH23-da VQGTTGVVWLRQPLDREAKSEMQVEFTVSDSQGVVKD---TVNIQIGDVNDNAP 107 CDH1-mu IERETGWLKVTQPLDREAIAKYILYSHAVSSNGEAVEDPMEIVITVTDQNDNRP 106 CDH2-mu INPISGQLSVTKPLDRELIARFHLRAHAVDINGNQVENPIDIVINVIDMNDNRP 106 :: :* : : :***** :.: : . :* .. .: * * * *** * B B Asp86 Asn3 Ca2 Ca5 Ca0 Ca3 Asp40 Ca1 Ca4 Arg4 C Asp36 Asp38 Eu Eu – Fig. 1. Structure of the CDH23 EC1 EC2 domains. (A) Sequence alignment of Fig. 2. Calcium binding motifs in CDH23. (A) Superimposition of the EC1– – the mature CDH23 EC1 EC2 domains from different species (hu, human; mu, EC2 junction of CDH23 (red) with the Ca2+ binding motifs at the C terminus fi 2+ murine; ch, chicken; da, zebra sh) with murine CDH1 and CDH2. Ca binding of EC2 (green). (B) Detail of the Ca2+ binding motif Ca0 at the N terminus of motifs are highlighted with gray boxes. Sequence differences between EC1 shown with corresponding 2Fo-Fc electron density at 1.1 Å resolution CDH23 molecules are indicated in green. The conserved Trp2 residue in CDH1 and contoured at 1.5 σ (red). and CDH2 is indicated in red. (B and C) Ribbon diagrams of CDH23 EC1–EC2: Ca2+-bound (B) and Eu2+-bound (C). Ca2+ is shown in yellow, Eu2+ in red. electron microscope as linear molecules (17), the linear align- – topology consisting of a sandwich of two β-sheets possessing three ment of CDH23 EC1 EC2 might have important functional (A, G, and F) and four (B, E, D, and C) β-strands, respectively. implications. However, it should be noted that in native tip links, Unlike in previously reported EC domain structures, there is also the extracellular domains of two CDH23 domains align in cis, an α-helix between strands C and D of EC1 (Fig. 1 B and C). which could lead to structural changes that affect the bend angle Typical
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