Structural basis for LAR-RPTP/Slitrk complex-mediated synaptic adhesion.
Synaptic adhesion molecules orchestrate synaptogenesis. The presynaptic leukocyte common antigen-related receptor protein tyrosine phosphatases (LAR-RPTPs) regulate synapse development by interacting with postsynaptic Slit- and Trk-like family proteins (Slitrks), which harbour two extracellular leucine-rich repeats (LRR1 and LRR2). Here we identify the minimal regions of the LAR-RPTPs and Slitrks, LAR-RPTPs Ig1-3 and Slitrks LRR1, for their interaction and synaptogenic function. Subsequent crystallographic and structure-guided functional analyses reveal that the splicing inserts in LAR-RPTPs are key molecular determinants for Slitrk binding and synapse formation. Moreover, structural comparison of the two Slitrk1 LRRs reveal that unique properties on the concave surface of Slitrk1 LRR1 render its specific binding to LAR-RPTPs. Finally, we demonstrate that lateral interactions between adjacent trans-synaptic LAR-RPTPs/Slitrks complexes observed in crystal lattices are critical for Slitrk1-induced lateral assembly and synaptogenic activity. Thus, we propose a model in which Slitrks mediate synaptogenic functions through direct binding to LAR-RPTPs and the subsequent lateral assembly of LAR-RPTPs/Slitrks complexes.
Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea.
Ji Won
JW
Um
Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Korea.
Kee Hun
KH
Kim
Department of Biomedical Laboratory Science, College of Health Science, Eulji University, Seongnam 461-713, Korea.
Beom Seok
BS
Park
1] Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Korea [2] Center for Synaptic Brain Dysfunctions, Institute for Basic Science (IBS), Daejeon 305-701, Korea.
Yeonsoo
Y
Choi
Center for Synaptic Brain Dysfunctions, Institute for Basic Science (IBS), Daejeon 305-701, Korea.
Doyoun
D
Kim
Graduate School of Nanoscience and Technology, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Republic of Korea.
Cha Yeon
CY
Kim
Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Korea.
Soo Jin
SJ
Kim
Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea.
Minhye
M
Kim
Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea.
Ji Seung
JS
Ko
Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Korea.
Seong-Gyu
SG
Lee
Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea.
Gayoung
G
Choii
1] Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Korea [2] Center for Synaptic Brain Dysfunctions, Institute for Basic Science (IBS), Daejeon 305-701, Korea.
Jungyong
J
Nam
1] Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Korea [2] Center for Cognition and Sociality, Institute for Basic Science (IBS), Daejeon 305-701, Korea.
Won Do
WD
Heo
1] Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Korea [2] Center for Synaptic Brain Dysfunctions, Institute for Basic Science (IBS), Daejeon 305-701, Korea.
Eunjoon
E
Kim
Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Korea.
Jie-Oh
JO
Lee
1] Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea [2] Department of Psychiatry, Yonsei University College of Medicine, Seoul 120-751, Korea.
Jaewon
J
Ko
Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Korea.
Ho Min
HM
Kim
D000818:Animals; D001665:Binding Sites; D002448:Cell Adhesion / Q000502:physiology; D057809:HEK293 Cells; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000378:metabolism / Q000502:physiology*; D017434:Protein Structure, Tertiary; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2 / Q000378:metabolism / Q000502:physiology*; D012097:Repressor Proteins / Q000378:metabolism / Q000502:physiology; D013569:Synapses / Q000378:metabolism* / Q000502:physiology
C464446:LRR1 protein, human; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D012097:Repressor Proteins; C505093:SLITRK1 protein, human; D017027:Protein Tyrosine Phosphatases; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2