A general model for preferential hetero-oligomerization of LIN-2/7 domains: mechanism underlying directed assembly of supramolecular signaling complexes.
LIN-2/7 (L27) domains are protein interaction modules that preferentially hetero-oligomerize, a property critical for their function in directing specific assembly of supramolecular signaling complexes at synapses and other polarized cell-cell junctions. We have solved the solution structure of the heterodimer composed of the L27 domains from LIN-2 and LIN-7. Comparison of this structure with other L27 domain structures has allowed us to formulate a general model for why most L27 domains form an obligate heterodimer complex. L27 domains can be divided in two types (A and B), with each heterodimer comprising an A/B pair. We have identified two keystone positions that play a central role in discrimination. The residues at these positions are energetically acceptable in the context of an A/B heterodimer, but would lead to packing defects or electrostatic repulsion in the context of A/A and B/B homodimers. As predicted by the model, mutations of keystone residues stabilize normally strongly disfavored homodimers. Thus, L27 domains are specifically optimized to avoid homodimeric interactions.
Petrosky
Keiko Y
KY
Biophysics Graduate Program, University of California, San Francisco, California 94143, USA.
Ou
Horng D
HD
Löhr
Frank
F
Dötsch
Volker
V
Lim
Wendell A
WA
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D017173:Caenorhabditis elegans / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000737:chemistry*; D002450:Cell Communication; D002942:Circular Dichroism; D003001:Cloning, Molecular; D004252:DNA Mutational Analysis; D019281:Dimerization; D000074288:Discs Large Homolog 1 Protein; D004305:Dose-Response Relationship, Drug; D019791:Guanidine / Q000737:chemistry; D015801:Helminth Proteins / Q000737:chemistry*; D006639:Histidine / Q000737:chemistry; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008565:Membrane Proteins / Q000737:chemistry*; D008958:Models, Molecular; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000737:chemistry; D010802:Phylogeny; D016133:Polymerase Chain Reaction; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D055672:Static Electricity; D013569:Synapses / Q000378:metabolism; D013696:Temperature
D048868:Adaptor Proteins, Signal Transducing; D029742:Caenorhabditis elegans Proteins; C513314:DLG1 protein, human; D000074288:Discs Large Homolog 1 Protein; D015801:Helminth Proteins; C099173:LIN-7 protein, C elegans; C097978:Lin-2 protein, C elegans; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D006639:Histidine; D019791:Guanidine