The cadherin superfamily of proteins is defined by the presence of extracellular cadherin (EC) "repeats" that engage in protein-protein interactions to mediate cell-cell adhesion, cell signaling, and mechanotransduction. The extracellular domains of nonclassical cadherins often have a large number of EC repeats along with other subdomains of various folds. Protocadherin-15 (PCDH15), a protein component of the inner-ear tip link filament essential for mechanotransduction, has 11 EC repeats and a membrane adjacent domain (MAD12) of atypical fold. Here we report the crystal structure of a pig PCDH15 fragment including EC10, EC11, and MAD12 in a parallel dimeric arrangement. MAD12 has a unique molecular architecture and folds as a ferredoxin-like domain similar to that found in the nucleoporin protein Nup54. Analytical ultracentrifugation experiments along with size-exclusion chromatography coupled to multiangle laser light scattering and small-angle x-ray scattering corroborate the crystallographic dimer and show that MAD12 induces parallel dimerization of PCDH15 near its membrane insertion point. In addition, steered molecular dynamics simulations suggest that MAD12 is mechanically weak and may unfold before tip-link rupture. Seq...Continue Reading
Multiple protein sequence alignment from tertiary structure comparison: assignment of global and residue confidence levels
Restoring low resolution structure of biological macromolecules from solution scattering using simulated annealing
Size-distribution analysis of macromolecules by sedimentation velocity ultracentrifugation and lamm equation modeling
Usher syndrome 1D and nonsyndromic autosomal recessive deafness DFNB12 are caused by allelic mutations of the novel cadherin-like gene CDH23
CDH23 mutation and phenotype heterogeneity: a profile of 107 diverse families with Usher syndrome and nonsyndromic deafness
Sedimentation velocity analysis of heterogeneous protein-protein interactions: Lamm equation modeling and sedimentation coefficient distributions c(s)
The tip-link antigen, a protein associated with the transduction complex of sensory hair cells, is protocadherin-15
PVS: a web server for protein sequence variability analysis tuned to facilitate conserved epitope discovery
Structure of the N terminus of cadherin 23 reveals a new adhesion mechanism for a subset of cadherin superfamily members
Nanomechanics of the cadherin ectodomain: "canalization" by Ca2+ binding results in a new mechanical element.
The extracellular architecture of adherens junctions revealed by crystal structures of type I cadherins
Characterizing flexible and intrinsically unstructured biological macromolecules by SAS using the Porod-Debye law
Mutations in protocadherin 15 and cadherin 23 affect tip links and mechanotransduction in mammalian sensory hair cells
Transforming binding affinities from three dimensions to two with application to cadherin clustering
Geneious Basic: an integrated and extendable desktop software platform for the organization and analysis of sequence data
Implementation and performance of SIBYLS: a dual endstation small-angle X-ray scattering and macromolecular crystallography beamline at the Advanced Light Source
Noddy, a mouse harboring a missense mutation in protocadherin-15, reveals the impact of disrupting a critical interaction site between tip-link cadherins in inner ear hair cells
Protein and ligand preparation: parameters, protocols, and influence on virtual screening enrichments
Targeted exon sequencing successfully discovers rare causative genes and clarifies the molecular epidemiology of Japanese deafness patients
Structure and Sequence Analyses of Clustered Protocadherins Reveal Antiparallel Interactions that Mediate Homophilic Specificity
Deciphering conformational transitions of proteins by small angle X-ray scattering and normal mode analysis
The physics of pulling polyproteins: a review of single molecule force spectroscopy using the AFM to study protein unfolding
Antiparallel protocadherin homodimers use distinct affinity- and specificity-mediating regions in cadherin repeats 1-4
Targeted Next-Generation Sequencing Successfully Detects Causative Genes in Chinese Patients with Hereditary Hearing Loss
Auditory cortex interneuron development requires cadherins operating hair-cell mechanoelectrical transduction
ATSAS 2.8: a comprehensive data analysis suite for small-angle scattering from macromolecular solutions
Adherens Junctions and Desmosomes Coordinate Mechanics and Signaling to Orchestrate Tissue Morphogenesis and Function: An Evolutionary Perspective
Structural relationship between the putative hair cell mechanotransduction channel TMC1 and TMEM16 proteins
Structural determinants of protocadherin-15 mechanics and function in hearing and balance perception
Single-molecule force spectroscopy reveals the dynamic strength of the hair-cell tip-link connection.
Adhesion Molecules in Health and Disease
Cell adhesion molecules are a subset of cell adhesion proteins located on the cell surface involved in binding with other cells or with the extracellular matrix in the process called cell adhesion. In essence, cell adhesion molecules help cells stick to each other and to their surroundings. Cell adhesion is a crucial component in maintaining tissue structure and function. Discover the latest research on adhesion molecule and their role in health and disease here.
An adherens junction is defined as a cell junction whose cytoplasmic face is linked to the actin cytoskeleton. They can appear as bands encircling the cell (zonula adherens) or as spots of attachment to the extracellular matrix (adhesion plaques). Adherens junctions uniquely disassemble in uterine epithelial cells to allow the blastocyst to penetrate between epithelial cells. Discover the latest research on adherens junctions here.
Cadherins and Catenins
Cadherins (named for "calcium-dependent adhesion") are a type of cell adhesion molecule (CAM) that is important in the formation of adherens junctions to bind cells with each other. Catenins are a family of proteins found in complexes with cadherin cell adhesion molecules of animal cells: alpha-catenin can bind to β-catenin and can also bind actin. β-catenin binds the cytoplasmic domain of some cadherins. Discover the latest research on cadherins and catenins here.