PDBsum entry 1olz

Developmental protein

PDB id: 1olz

Contents

Protein chains

622 a.a. *

Waters ×841

* Residue conservation analysis

References listed in PDB file

Key reference

Title

The ligand-Binding face of the semaphorins revealed by the high-Resolution crystal structure of sema4d.

Authors

C.A.Love, K.Harlos, N.Mavaddat, S.J.Davis, D.I.Stuart, E.Y.Jones, R.M.Esnouf.

Ref.

Nat Struct Biol, 2003, 10, 843-848. [DOI no: 10.1038/nsb977]

PubMed id

12958590

Abstract

Semaphorins, proteins characterized by an extracellular sema domain, regulate axon guidance, immune function and angiogenesis. The crystal structure of SEMA4D (residues 1-657) shows the sema topology to be a seven-bladed beta-propeller, revealing an unexpected homology with integrins. The sema beta-propeller contains a distinctive 77-residue insertion between beta-strands C and D of blade 5. Blade 7 is followed by a domain common to plexins, semaphorins and integrins (PSI domain), which forms a compact cysteine knot abutting the side of the propeller, and an Ig-like domain. The top face of the beta-propeller presents prominent loops characteristic of semaphorins. In addition to limited contact between the Ig-like domains, the homodimer is stabilized through extensive interactions between the top faces in a sector of the beta-propeller used for heterodimerization in integrins. This face of the propeller also mediates ligand binding in integrins, and functional data for semaphorin-receptor interactions map to the equivalent surface.

Figure 1.
Figure 1. The crystal structure of sSEMA4D. (a) Schematic of the homodimer. For one subunit the -propeller is colored from blue at the N terminus to red at the C terminus; the extrusion (at top), the PSI and the Ig-like domains (at bottom) are magenta, pink and coral, respectively. (b) The sSEMA4D subunit labeled to indicate secondary structure nomenclature and domains. Disulfide bonds are yellow. Orientation and color coding are as in a. (c) The top and bottom surfaces of the -propeller. Distinctive loops at the top surface are color coded as in a, and the side chains of key solvent-exposed residues are shown as ball-and-stick. The orientation is rotated by 90° about the horizontal relative to that in a. (d) The interaction of 4B-C loops, which forms the heart of the dimerization interface. The solvent-accessible surface for one of the subunits is rendered as a semitransparent surface. Residues are shown as ball-and-stick with color coding for one subunit as in a. The orientation is rotated by 90° about the vertical relative to that in a.

Figure 2.
Figure 2. Structural and sequence alignments of the semaphorins and integrins. (a) Sequence alignments for the sema domain. For the semaphorin sequences the extrusion and PSI domains are boxed in blue and coral, respectively. Residues contributing to the homodimerization interface in sSEMA4D are highlighted in pink. A 70-residue section of the SEMA3A sequence implicated in receptor specificity is green24. Residues that abolish function when mutated in SEMA3A are cyan. Residues in SEMA3B and SEMA3F implicated in cancer biology45, 46 (S. Naylor, personal communication) are yellow.Secondary structure definitions for sSEMA4D are above the sequence alignment, whereas those for the integrin V subunit (ITAV) are below. Cysteines conserved in the semaphorins are highlighted in coral, and those conserved between the semaphorins and integrin are in red. The figure was produced using ESPript (http://prodes.toulouse.inra.fr/ESPript/). (b) Structural comparison of the SEMA4D homodimer and integrin V 3 heterodimer. Structures are shown with equivalent propeller orientations and, for clarity, include only the sema propeller domains and the integrin propeller and A domain core. Color coding for the reference propeller is as for Figure 1a.

The above figures are reprinted by permission from Macmillan Publishers Ltd: Nat Struct Biol (2003, 10, 843-848) copyright 2003.