Family-wide Structural and Biophysical Analysis of Binding Interactions among Non-clustered δ-Protocadherins
Summary: Non-clustered δ1- and δ2-protocadherins, close relatives of clustered protocadherins, function in cell adhesion and motility and play essential roles in neural patterning. To understand the molecular interactions underlying these functions, we used solution biophysics to characterize bindin...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2020-02-01
|
| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124720301571 |
| _version_ | 1818133741852164096 |
|---|---|
| author | Oliver J. Harrison Julia Brasch Phinikoula S. Katsamba Goran Ahlsen Alex J. Noble Hanbin Dan Rosemary V. Sampogna Clinton S. Potter Bridget Carragher Barry Honig Lawrence Shapiro |
| author_facet | Oliver J. Harrison Julia Brasch Phinikoula S. Katsamba Goran Ahlsen Alex J. Noble Hanbin Dan Rosemary V. Sampogna Clinton S. Potter Bridget Carragher Barry Honig Lawrence Shapiro |
| author_sort | Oliver J. Harrison |
| collection | DOAJ |
| description | Summary: Non-clustered δ1- and δ2-protocadherins, close relatives of clustered protocadherins, function in cell adhesion and motility and play essential roles in neural patterning. To understand the molecular interactions underlying these functions, we used solution biophysics to characterize binding of δ1- and δ2-protocadherins, determined crystal structures of ectodomain complexes from each family, and assessed ectodomain assembly in reconstituted intermembrane junctions by cryoelectron tomography (cryo-ET). Homophilic trans (cell–cell) interactions were preferred for all δ-protocadherins, with additional weaker heterophilic interactions observed exclusively within each subfamily. As expected, δ1- and δ2-protocadherin trans dimers formed through antiparallel EC1–EC4 interfaces, like clustered protocadherins. However, no ectodomain-mediated cis (same-cell) interactions were detectable in solution; consistent with this, cryo-ET of reconstituted junctions revealed dense assemblies lacking the characteristic order observed for clustered protocadherins. Our results define non-clustered protocadherin binding properties and their structural basis, providing a foundation for interpreting their functional roles in neural patterning. : Non-clustered δ-protocadherins are adhesion molecules linked to a number of neurological disorders. Harrison et al. apply biophysical and structural methods across the family to show preferential self-binding through a canonical interface and disordered assemblies of adhesive dimers between membranes that diverge from ordered assemblies of close relatives clustered protocadherins. Keywords: cell adhesion, non-clustered protocadherins, cadherin, X-ray crystallography, cryo-electron tomography, homophilic adhesion, neuronal cell adhesion |
| first_indexed | 2024-12-11T08:57:33Z |
| format | Article |
| id | doaj.art-8f90b79156da49fcad93fd395bf1ec18 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-11T08:57:33Z |
| publishDate | 2020-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-8f90b79156da49fcad93fd395bf1ec182022-12-22T01:13:50ZengElsevierCell Reports2211-12472020-02-0130826552671.e7Family-wide Structural and Biophysical Analysis of Binding Interactions among Non-clustered δ-ProtocadherinsOliver J. Harrison0Julia Brasch1Phinikoula S. Katsamba2Goran Ahlsen3Alex J. Noble4Hanbin Dan5Rosemary V. Sampogna6Clinton S. Potter7Bridget Carragher8Barry Honig9Lawrence Shapiro10Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA; Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10027, USADepartment of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA; Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10027, USA; National Resource for Automated Molecular Microscopy, Simons Electron Microscopy Center, New York Structural Biology Center, New York, NY 10027, USADepartment of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA; Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10027, USADepartment of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA; Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10027, USANational Resource for Automated Molecular Microscopy, Simons Electron Microscopy Center, New York Structural Biology Center, New York, NY 10027, USADepartment of Medicine, Division of Nephrology, Columbia University, New York, NY 10032, USADepartment of Medicine, Division of Nephrology, Columbia University, New York, NY 10032, USADepartment of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA; National Resource for Automated Molecular Microscopy, Simons Electron Microscopy Center, New York Structural Biology Center, New York, NY 10027, USADepartment of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA; National Resource for Automated Molecular Microscopy, Simons Electron Microscopy Center, New York Structural Biology Center, New York, NY 10027, USADepartment of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA; Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10027, USA; Department of Medicine, Division of Nephrology, Columbia University, New York, NY 10032, USA; Department of Systems Biology, Columbia University, New York, NY 10032, USA; Corresponding authorDepartment of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA; Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10027, USA; Corresponding authorSummary: Non-clustered δ1- and δ2-protocadherins, close relatives of clustered protocadherins, function in cell adhesion and motility and play essential roles in neural patterning. To understand the molecular interactions underlying these functions, we used solution biophysics to characterize binding of δ1- and δ2-protocadherins, determined crystal structures of ectodomain complexes from each family, and assessed ectodomain assembly in reconstituted intermembrane junctions by cryoelectron tomography (cryo-ET). Homophilic trans (cell–cell) interactions were preferred for all δ-protocadherins, with additional weaker heterophilic interactions observed exclusively within each subfamily. As expected, δ1- and δ2-protocadherin trans dimers formed through antiparallel EC1–EC4 interfaces, like clustered protocadherins. However, no ectodomain-mediated cis (same-cell) interactions were detectable in solution; consistent with this, cryo-ET of reconstituted junctions revealed dense assemblies lacking the characteristic order observed for clustered protocadherins. Our results define non-clustered protocadherin binding properties and their structural basis, providing a foundation for interpreting their functional roles in neural patterning. : Non-clustered δ-protocadherins are adhesion molecules linked to a number of neurological disorders. Harrison et al. apply biophysical and structural methods across the family to show preferential self-binding through a canonical interface and disordered assemblies of adhesive dimers between membranes that diverge from ordered assemblies of close relatives clustered protocadherins. Keywords: cell adhesion, non-clustered protocadherins, cadherin, X-ray crystallography, cryo-electron tomography, homophilic adhesion, neuronal cell adhesionhttp://www.sciencedirect.com/science/article/pii/S2211124720301571 |
| spellingShingle | Oliver J. Harrison Julia Brasch Phinikoula S. Katsamba Goran Ahlsen Alex J. Noble Hanbin Dan Rosemary V. Sampogna Clinton S. Potter Bridget Carragher Barry Honig Lawrence Shapiro Family-wide Structural and Biophysical Analysis of Binding Interactions among Non-clustered δ-Protocadherins Cell Reports |
| title | Family-wide Structural and Biophysical Analysis of Binding Interactions among Non-clustered δ-Protocadherins |
| title_full | Family-wide Structural and Biophysical Analysis of Binding Interactions among Non-clustered δ-Protocadherins |
| title_fullStr | Family-wide Structural and Biophysical Analysis of Binding Interactions among Non-clustered δ-Protocadherins |
| title_full_unstemmed | Family-wide Structural and Biophysical Analysis of Binding Interactions among Non-clustered δ-Protocadherins |
| title_short | Family-wide Structural and Biophysical Analysis of Binding Interactions among Non-clustered δ-Protocadherins |
| title_sort | family wide structural and biophysical analysis of binding interactions among non clustered δ protocadherins |
| url | http://www.sciencedirect.com/science/article/pii/S2211124720301571 |
| work_keys_str_mv | AT oliverjharrison familywidestructuralandbiophysicalanalysisofbindinginteractionsamongnonclustereddprotocadherins AT juliabrasch familywidestructuralandbiophysicalanalysisofbindinginteractionsamongnonclustereddprotocadherins AT phinikoulaskatsamba familywidestructuralandbiophysicalanalysisofbindinginteractionsamongnonclustereddprotocadherins AT goranahlsen familywidestructuralandbiophysicalanalysisofbindinginteractionsamongnonclustereddprotocadherins AT alexjnoble familywidestructuralandbiophysicalanalysisofbindinginteractionsamongnonclustereddprotocadherins AT hanbindan familywidestructuralandbiophysicalanalysisofbindinginteractionsamongnonclustereddprotocadherins AT rosemaryvsampogna familywidestructuralandbiophysicalanalysisofbindinginteractionsamongnonclustereddprotocadherins AT clintonspotter familywidestructuralandbiophysicalanalysisofbindinginteractionsamongnonclustereddprotocadherins AT bridgetcarragher familywidestructuralandbiophysicalanalysisofbindinginteractionsamongnonclustereddprotocadherins AT barryhonig familywidestructuralandbiophysicalanalysisofbindinginteractionsamongnonclustereddprotocadherins AT lawrenceshapiro familywidestructuralandbiophysicalanalysisofbindinginteractionsamongnonclustereddprotocadherins |