Structure of a cyclic nucleotide-regulated

Title: Structure of a cyclic nucleotide-regulated potassium channel

Speaker: João Henrique Morais Cabral

Affiliation: Instituto de Biologia Molecular e Celular

Host: Margarida Archer

Abstract

The 6 TM tetrameric cation channels form the largest ion channel family, some members of which are voltage-gated and others are not. There are no reported channel structures to match the wealth of functional data on the non voltage-gated members. We have determined the structure of the trans-membrane regions of the bacterial cyclic nucleotide regulated channel MlotiK1, a non-voltage gated 6 TM channel. The structure shows how the S1-S4 domain and its associated linker can serve as a clamp to constrain the pore’s gate and possibly function in concert with ligand binding domains to regulate the opening the pore. The structure also leads us to hypothesize a new mechanism by which motions of the S6 inner helices can gate ion conduction pathway at a position along the pore closer to the selectivity filter than the canonical helix bundle crossing.

Short CV

Work address: IBMC Rua Campo Alegre, 823, Porto 4150-180   Portugal
Tel: +351 226 074 900 ext: 1450
Email: jcabral@ibmc.up.pt

Citizenship: Portuguese

Date of birth: 02/04/65

Education and research experience:
1983/87: ”Licenciatura” in Biochemistry, Universidade do Porto, Porto, Portugal
1987/88: Research assistant at the Analytical section, Dept. of Chemistry, Universidade do Porto, Porto, Portugal
1988/93: Awarded a Ph.D. degree at the University of Edinburgh, Edinburgh,UK
1994/95: Post-doctoral Research Fellow with Prof. Robert Liddington at the Dana-Farber Cancer Institute/Harvard University, Boston, USA.
1996/97: Post-doctoral Research Associate with Prof. Robert Liddington at the Biochemistry Department, University of Leicester, Leicester, UK
1997/2000: Post-doctoral Research Associate with Prof. Roderick MacKinnon at Rockefeller University, New York, USA.
2001-2006: Assistant professor at the Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT
2007-2008 Associate Professor at the Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT
2008-  Principal Investigator at the Instituto de Biological Molecular e Celular, Porto, Portugal
Publications:

Undergraduate student:
Morais Cabral, J.H., Damas, A.M., Moradas Ferreira, P. “The effect of spectrin on erythrocyte membrane order. A study using ESR spectroscopy”. Revista Portuguesa de Química (1988), 20, 46-52

Graduate Student:
Sawyer, L., Morais Cabral, J.H., Batt, C.A., “Protein engineering studies of Beta-lactoglubulin”, in Biochemistry of Milk Products (1994) (ed. Andrews, A.T. and Varley, J.), Royal Society of Chemistry 114-126

Morais Cabral, J.H., Atkins, G.L., Sánchez, L.M., López-Boado, Y.S., López-Otìn, C., Sawyer, L., “Arachidonic acid binds to apolipoprotein D: implications for the protein function” FEBS Letters (1995), 366, 53-56

Brownlow, S., Morais Cabral, J.H., Cooper, R., Flower, D.R., Yewdall, S.J., Polikarpov, I., North, A.C.T., Sawyer, L. “Bovine alfa-lactoglobulin at 1.8Å resolution – still an enigmatic lipocalin” Structure (1997), 5, 481-495

Postdoctoral scientist:
Morais Cabral, J.H., Petosa, C., Raza, S., Sutcliffe, M., Byron, O., Poy, F., Marfatia, S., Chishti, A., Liddington, R., “Structure of a PDZ domain” Nature (1996), 382, 649-652

Marfatia, S.M., Morais Cabral, J.H., Lin, L., Hough, C., Bryant, P.J., Stolz, L., Chishti, A., “Molecular organization of the PDZ domains in the Human Discs-Large protein suggest a mechanism for coupling PDZ domain-binding proteins to ATP and membrane cytoskeleton” J. Cell Biology (1996), 135, 753-766

Morais Cabral, J.H., Jackson, A.P., Smith, C.V., Shikotra, N., Maxwell, A., Liddington, R. “Crystal structure of the Breakage-reunion domain of DNA gyrase” Nature (1997), 388, 903-906

Marfatia, S.M., Morais Cabral, J.H., Kin, A.C., Byron, O., Chishti, A. “The PDZ domain of the Human erythrocyte p55 mediates its binding to the cytoplasmic carboxyl-terminus of glycophorin C” J. Biological Chemistry (1997), 272, 24191-24197

Doyle, D.A., Morais Cabral, J., Pfuetzner, R.A., Kuo, A., Gulbis, J.M., Cohen, S.L., Chait, B.T., MacKinnon, R. “The structure of the potassium channel: molecular basis of K+ conduction and selectivity“ Science (1998), 280, 69-77  
 
Morais Cabral J.H., Lee A., Cohen S.L., Chait B.T., Li M., Mackinnon R. “Crystal structure and functional analysis of the HERG potassium channel N terminus: a
eukaryotic PAS domain” Cell (1998), 95, 649-655

Zhou M., Morais Cabral J.H., Mann S., Mackinnon R. “Potassium channel receptor site for the inactivation gate and quaternary amine inhibitors” Nature (2001), 411, 657-661

Zhou Y., Morais Cabral J.H., Kaufman A., Mackinnon R. “Chemistry of ion hydration and coordination revealed by a K+ channel-Fab complex structure” Nature (2001), 414, 43-48

Morais Cabral J.H., Zhou Y., Mackinnon R. “Energetic optimization of ion conduction rate by the K+ selectivity filter” Nature (2001), 414, 37-42

Independent Investigator:
Clayton G., Silverman W., Heginbotham L., Morais Cabral J.H. “Structural basis of activation of a bacterial cyclic nucleotide regulated potassium channel” Cell (2004), 119:615-27.

Albright RA, Vazquez Ibar JL, Kim CU,Gruner SM, Morais Cabral JH ”The RCK domain of the KtrAB K+ transporter: multiple conformations of an octameric ring.” Cell (2006), 126: 1147-59

Albright RA, Joh K, Morais-Cabral JH. ”Probing the structure of the dimeric KtrB membrane protein.” J Biol Chem. (2007), 282: 35046-55

Clayton GM, Altieri S, Heginbotham L, Unger VM, Morais-Cabral JH “Structure of the transmembrane regions of a bacterial cyclic nucleotide-regulated channel” Proc Natl Acad Sci USA January 2008 (in press).