Structural basis of diverse membrane target recognitions by ankyrins.
Ankyrin adaptors together with their spectrin partners coordinate diverse ion channels and cell adhesion molecules within plasma membrane domains and thereby promote physiological activities including fast signaling in the heart and nervous system. Ankyrins specifically bind to numerous membrane targets through their 24 ankyrin repeats (ANK repeats), although the mechanism for the facile and independent evolution of these interactions has not been resolved. Here we report the structures of ANK repeats in complex with an inhibitory segment from the C-terminal regulatory domain and with a sodium channel Nav1.2 peptide, respectively, showing that the extended, extremely conserved inner groove spanning the entire ANK repeat solenoid contains multiple target binding sites capable of accommodating target proteins with very diverse sequences via combinatorial usage of these sites. These structures establish a framework for understanding the evolution of ankyrins' membrane targets, with implications for other proteins containing extended ANK repeat domains.
Division of Life Science, State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Hong Kong, Hong Kong.
Chao
C
Wang
Division of Life Science, State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Hong Kong, Hong Kong.
Zhiyi
Z
Wei
Division of Life Science, State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Hong Kong, Hong Kong.
Keyu
K
Chen
Division of Life Science, State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Hong Kong, Hong Kong.
Fei
F
Ye
Division of Life Science, State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Hong Kong, Hong Kong.
Cong
C
Yu
Department of Biochemistry, Howard Hughes Medical Institute, Duke University Medical Center, Durham, United States.
Vann
V
Bennett
Division of Life Science, State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Hong Kong, Hong Kong.
Mingjie
M
Zhang
D000595:Amino Acid Sequence; D000818:Animals; D017089:Ankyrin Repeat; D017487:Ankyrins / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D002462:Cell Membrane / Q000737:chemistry*; D017124:Conserved Sequence; D018360:Crystallography, X-Ray; D005454:Fluorescence Polarization; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D009414:Nerve Growth Factors / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D015222:Sodium Channels; D013329:Structure-Activity Relationship
D017487:Ankyrins; D009414:Nerve Growth Factors; D015222:Sodium Channels; D018698:Glutamic Acid
ANK1/ANK2/ANK3; L1CAM; ankyrin repeats; axon initial segment; biochemistry; biophysics; none; sodium channel; structural biology