Structure of the human discs large 1 PDZ2- adenomatous polyposis coli cytoskeletal polarity complex: insight into peptide engagement and PDZ clustering

PLoS One. 2012;7(11):e50097. doi: 10.1371/journal.pone.0050097. Epub 2012 Nov 19.

Abstract

The membrane associated guanylate kinase (MAGUK) family member, human Discs Large 1 (hDlg1) uses a PDZ domain array to interact with the polarity determinant, the Adenomatous Polyposis Coli (APC) microtubule plus end binding protein. The hDLG1-APC complex mediates a dynamic attachment between microtubule plus ends and polarized cortical determinants in epithelial cells, stem cells, and neuronal synapses. Using its multi-domain architecture, hDlg1 both scaffolds and regulates the polarity factors it engages. Molecular details underlying the hDlg1-APC interaction and insight into how the hDlg1 PDZ array may cluster and regulate its binding factors remain to be determined. Here, I present the crystal structure of the hDlg1 PDZ2-APC complex and the molecular determinants that mediate APC binding. The hDlg1 PDZ2-APC complex also provides insight into potential modes of ligand-dependent PDZ domain clustering that may parallel Dlg scaffold regulatory mechanisms. The hDlg1 PDZ2-APC complex presented here represents a core biological complex that bridges polarized cortical determinants with the dynamic microtubule cytoskeleton.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / chemistry*
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Adenomatous Polyposis Coli Protein / chemistry*
  • Adenomatous Polyposis Coli Protein / genetics
  • Adenomatous Polyposis Coli Protein / metabolism
  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Crystallization
  • Crystallography, X-Ray
  • Cytoskeleton / chemistry*
  • Cytoskeleton / metabolism
  • Discs Large Homolog 1 Protein
  • Epithelial Cells / chemistry
  • Epithelial Cells / metabolism
  • Escherichia coli / genetics
  • Gene Expression
  • Humans
  • Membrane Proteins / chemistry*
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Models, Molecular
  • Molecular Sequence Data
  • PDZ Domains
  • Peptides / chemistry*
  • Peptides / genetics
  • Peptides / metabolism
  • Protein Binding
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Sequence Alignment
  • Stem Cells / chemistry
  • Stem Cells / metabolism

Substances

  • APC protein, human
  • Adaptor Proteins, Signal Transducing
  • Adenomatous Polyposis Coli Protein
  • DLG1 protein, human
  • Discs Large Homolog 1 Protein
  • Membrane Proteins
  • Peptides
  • Recombinant Proteins

Associated data

  • PDB/4G69