PDBsum entry 2v5m

Cell adhesion

PDB id: 2v5m

Contents

Protein chain

388 a.a. *

Ligands

NAG-NAG ×2

GOL

Waters ×709

* Residue conservation analysis

PDB id:

2v5m

Name:

Cell adhesion

Title:

Structural basis for dscam isoform specificity

Structure:

Dscam. Chain: a. Fragment: n-terminal four domains (d1, d2, d3 and d4), residues 36- 423. Synonym: down syndrome cell adhesion molecule dscam. Engineered: yes. Other_details: isoform 4.1/6.34

Source:

Drosophila melanogaster. Fruit fly. Organism_taxid: 7227. Variant: splicing variant 4.1/6.34. Organ: brain. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf9.

Resolution:

1.95Å R-factor: 0.171 R-free: 0.205

Authors:

R.Meijers,R.Puettmann-Holgado,G.Skiniotis,J.-H.Liu,T.Walz, D.Schmucker,J.-H.Wang

Key ref:

R.Meijers et al. (2007). Structural basis of Dscam isoform specificity. Nature, 449, 487-491. PubMed id: 17721508 DOI: 10.1038/nature06147

Date:

06-Jul-07 Release date: 11-Sep-07

Protein chain

Q0E9H9  (Q0E9H9_DROME) -  Cell adhesion molecule Dscam1 from Drosophila melanogaster

Seq: 2016 a.a.

Struc: 388 a.a.*

* PDB and UniProt seqs differ at 21 residue positions (black crosses)

DOI no: 10.1038/nature06147

Nature 449:487-491 (2007)

PubMed id: 17721508

Structural basis of Dscam isoform specificity.

R.Meijers, R.Puettmann-Holgado, G.Skiniotis, J.H.Liu, T.Walz, J.H.Wang, D.Schmucker.

ABSTRACT

The Dscam gene gives rise to thousands of diverse cell surface receptors thought to provide homophilic and heterophilic recognition specificity for neuronal wiring and immune responses. Mutually exclusive splicing allows for the generation of sequence variability in three immunoglobulin ecto-domains, D2, D3 and D7. We report X-ray structures of the amino-terminal four immunoglobulin domains (D1-D4) of two distinct Dscam isoforms. The structures reveal a horseshoe configuration, with variable residues of D2 and D3 constituting two independent surface epitopes on either side of the receptor. Both isoforms engage in homo-dimerization coupling variable domain D2 with D2, and D3 with D3. These interactions involve symmetric, antiparallel pairing of identical peptide segments from epitope I that are unique to each isoform. Structure-guided mutagenesis and swapping of peptide segments confirm that epitope I, but not epitope II, confers homophilic binding specificity of full-length Dscam receptors. Phylogenetic analysis shows strong selection of matching peptide sequences only for epitope I. We propose that peptide complementarity of variable residues in epitope I of Dscam is essential for homophilic binding specificity.

Selected figure(s)

Figure 1.
Figure 1: Structure of the N-terminal four-domain fragment of Dscam. a, Representative class averages from negatively stained Dscam D1–D8[1.34.30] show that the molecule can adopt different conformations but retains the horseshoe configuration of the N-terminal D1–D4 domains. Scale bar, 10 nm. b, Representative class averages from negatively stained Dscam D1–D4[1.34] show that the four domains of Dscam D1–D4[1.34] are arranged in a horseshoe configuration. Scale bar, 5 nm. c, Ribbon diagram of Dscam D1–D4[1.34] coloured according to sequence variability; conserved residues are coloured cyan, variable residues are green and hypervariable residues are red. The variability was calculated using Shannon's uncertainty^22, and residues were classified as hypervariable if the uncertainty value exceeded two-thirds of the highest value observed for all residues from exons 4 and 6. d, e, Surface representation of epitope I (left) and II (right) on either side of the horseshoe for Dscam D1–D4[1.34] (d) and Dscam D1–D4[9.9] (e). Colour codes are as in c. The figure was prepared using PyMOL (http://www.pymol.org).

Figure 2.
Figure 2: Homophilic dimers observed in the crystal lattice. a, b, Ribbon diagram of the dimer in Dscam D1–D4[1.34] (a) and Dscam D1–D4[9.9 ](b). D1 and D4, green; D2 and D3, blue for monomer A; D1 and D4, yellow; D2 and D3, cyan for monomer B. Residues at symmetry centre are underlined. The isoform-specific interaction elements are shown as red and orange in molecules A and B, respectively, and are displayed in more detail along their respective twofold axes: c, the D2^A–D2^B interface of Dscam D1–D4[1.34]; d, the D2^A–D2^B interface of Dscam D1–D4[9.9] (blue and cyan residues are constant); e, the D3^A–D3^B interface of Dscam D1–D4[1.34]; f, the D3^A–D3^B interface of Dscam D1–D4[9.9]. Residues involved in dimer-sustaining hydrogen bonds are labelled and the dyad axes are displayed as black ellipsoids. The figure was prepared using PyMOL (http://www.pymol.org).

The above figures are reprinted by permission from Macmillan Publishers Ltd: Nature (2007, 449, 487-491) copyright 2007.

Figures were selected by the author.