Complex between nidogen and laminin fragments reveals a paradigmatic β-propeller interface

Basement membranes are fundamental to tissue organization and physiology in all metazoans. The interaction between laminin and nidogen is crucial to the assembly of basement membranes. The structure of the interacting domains reveals a six-bladed Tyr-Trp-Thr-Asp (YWTD) β-propeller domain in nidogen bound to laminin epidermal-growth-factor-like (LE) modules III3–5 in laminin (LE3–5). Laminin LE module 4 binds to an amphitheatre-shaped surface on the pseudo-6-fold axis of the β-propeller, and LE module 3 binds over its rim. A Phe residue that shutters the water-filled central aperture of the β-propeller, the rigidity of the amphitheatre, and high shape complementarity enable the construction of an evolutionarily conserved binding surface for LE4 of unprecedentedly high affinity for its small size. Hypermorphic mutations in the Wnt co-receptor LRP5 (refs 6–9) suggest that a similar YWTD β-propeller interface is used to bind ligands that function in developmental pathways. A related interface, but shifted off-centre from the pseudo-6-fold axis and lacking the shutter over the central aperture, is used in the low-density lipoprotein receptor for an intramolecular interaction that is regulated by pH in receptor recycling.

[1]  T. Blundell,et al.  Comparative protein modelling by satisfaction of spatial restraints. , 1993, Journal of molecular biology.

[2]  D. Strickland,et al.  Diverse roles for the LDL receptor family , 2002, Trends in Endocrinology & Metabolism.

[3]  C. Chothia,et al.  The atomic structure of protein-protein recognition sites. , 1999, Journal of molecular biology.

[4]  Joseph L. Goldstein,et al.  Structure of the LDL Receptor Extracellular Domain at Endosomal pH , 2002, Science.

[5]  R. Timpl,et al.  Specific ablation of the nidogen-binding site in the laminin gamma1 chain interferes with kidney and lung development. , 2002, Development.

[6]  R. Timpl,et al.  Structural and Genetic Analysis of Laminin‐Nidogen Interaction , 1998, Annals of the New York Academy of Sciences.

[7]  Miikka Vikkula,et al.  LDL Receptor-Related Protein 5 (LRP5) Affects Bone Accrual and Eye Development , 2001, Cell.

[8]  H. Wolfson,et al.  Shape complementarity at protein–protein interfaces , 1994, Biopolymers.

[9]  H. Bock,et al.  Lipoprotein receptors in the nervous system. , 2002, Annual review of biochemistry.

[10]  M. Paulsson,et al.  The Absence of Nidogen 1 Does Not Affect Murine Basement Membrane Formation , 2000, Molecular and Cellular Biology.

[11]  R. Timpl,et al.  Gene Structure and Functional Analysis of the Mouse Nidogen-2 Gene: Nidogen-2 Is Not Essential for Basement Membrane Formation in Mice , 2002, Molecular and Cellular Biology.

[12]  Hyesung Jeon,et al.  Implications for familial hypercholesterolemia from the structure of the LDL receptor YWTD-EGF domain pair , 2001, Nature Structural Biology.

[13]  P Bork,et al.  Structure and distribution of modules in extracellular proteins , 1996, Quarterly Reviews of Biophysics.

[14]  J. Kuszak,et al.  Neurologic Defects and Selective Disruption of Basement Membranes in Mice Lacking Entactin-1/Nidogen-1 , 2002, Laboratory Investigation.

[15]  R. Timpl,et al.  Drosophila laminin binds to mammalian nidogen and to heparan sulfate proteoglycan. , 1997, European journal of biochemistry.

[16]  Richard P Lifton,et al.  High bone density due to a mutation in LDL-receptor-related protein 5. , 2002, The New England journal of medicine.

[17]  R J Read,et al.  Crystallography & NMR system: A new software suite for macromolecular structure determination. , 1998, Acta crystallographica. Section D, Biological crystallography.

[18]  R. Timpl,et al.  A single EGF‐like motif of laminin is responsible for high affinity nidogen binding. , 1993, The EMBO journal.

[19]  R. Huber,et al.  Structure of the nidogen binding LE module of the laminin gamma1 chain in solution. , 1996, Journal of molecular biology.

[20]  R. Timpl,et al.  Properties of the extracellular calcium binding module of the proteoglycan testican , 1997, FEBS letters.

[21]  J. Navaza,et al.  AMoRe: an automated package for molecular replacement , 1994 .

[22]  R. Huber,et al.  Site‐directed mutagenesis and structural interpretation of the nidogen binding site of the laminin gamma1 chain. , 1996, The EMBO journal.

[23]  Z. Otwinowski,et al.  Processing of X-ray diffraction data collected in oscillation mode. , 1997, Methods in enzymology.

[24]  R. Huber,et al.  Crystal structure of three consecutive laminin-type epidermal growth factor-like (LE) modules of laminin gamma1 chain harboring the nidogen binding site. , 1996, Journal of molecular biology.

[25]  Jens Bollerslev,et al.  Six novel missense mutations in the LDL receptor-related protein 5 (LRP5) gene in different conditions with an increased bone density. , 2003, American journal of human genetics.

[26]  T. Kreis,et al.  Guidebook to the extracellular matrix, anchor, and adhesion proteins , 1999 .

[27]  T. Springer An Extracellular b-Propeller Module Predicted in Lipoprotein and Scavenger Receptors, Tyrosine Kinases, Epidermal Growth Factor Precursor, and Extracellular Matrix Components , 1998 .

[28]  T. Springer,et al.  An extracellular beta-propeller module predicted in lipoprotein and scavenger receptors, tyrosine kinases, epidermal growth factor precursor, and extracellular matrix components. , 1998, Journal of molecular biology.

[29]  R. Timpl,et al.  Two non‐contiguous regions contribute to nidogen binding to a single EGF‐like motif of the laminin gamma 1 chain. , 1994, The EMBO journal.

[30]  Richard O. Hynes,et al.  The Evolution of Cell Adhesion , 2000, The Journal of cell biology.

[31]  Mark L. Johnson,et al.  High bone density due to a mutation in LDL-receptor-related protein 5. , 2002, The New England journal of medicine.

[32]  Mark L. Johnson,et al.  A mutation in the LDL receptor-related protein 5 gene results in the autosomal dominant high-bone-mass trait. , 2002, American journal of human genetics.