Where Ideas Grow

Structural Biochemistry

ABOUT

We are generally interested on the mechanisms of ion transport across the cell membrane. We have two active research lines, the characterization of the molecular properties of KCNH channels, a family of eukaryotic K+ channels, and the study of the mechanisms that regulate the intracellular concentration of potassium ion in bacteria.

 

RESEARCH

KCNH channels: KCNH channels have important roles in neuronal excitability, cardiac repolarization and cell proliferation. The human ERG (hERG) K+ channel conducts a cardiac repolarizing current and mutations or channel block cause long QT syndrome (LQTS) and catastrophic ventricular arrhythmias. We have developed single-chain antibody fragments (scFv) that bind to the intracellular PAS domain of the hERG channel and modulate its functional properties. These studies suggest that the interactions established by the PAS domain with the rest of the channel are dynamic, changing with the functional states of the channel. Moreover, the scFv molecules increased the amount of current conducted by hERG and shortened the Action Potential Duration in cardiomyocytes, demonstrating therapeutic potential. We are now using these molecules to explore the mechanism of hERG activation.

 

Regulation of intracellular K+ in bacteria: All organisms on Earth accumulate large amounts of K+ inside the cell. In bacteria, intracellular K+ has a role in determining intracellular pressure (turgor), pH and membrane potential. In addition, regulation of intracellular K+ is essential for bacteria to adapt to extracellular changes. Our studies are focused in understanding the molecular properties of K+ transporters that mediate inward and outward ion movement and how these opposing activities are balanced to allow a controlled amount of K+ inside the cell. This fundamental understanding is crucial to define if these transporter systems are potential candidates for anti-microbial strategies.

Cartoon representation of the crystal structure of the MlotiK1 potassium channel with pore domain in grey, S1-S4 domain in red and K+ as magenta spheres. Putative membrane limits are indicated by horizontal lines.

Team

Selected Publications

Zhao Y., Goldschen-Ohm M.P., Morais-Cabral J.H., Chanda B., Robertson G.A.,
The intrinsically liganded cyclic nucleotide-binding homology domain promotes KCNH channel activation. Journal of General Physiology149(2):249-260, 2017. [Journal: Article] [CI: 17] [IF: 3,7]
DOI: 10.1085/jgp.201611701 SCOPUS: 85012914073. Journal of General Physiology. 2017

Szollosi A., Vieira-Pires R.S., Teixeira-Duarte C.M., Rocha R., Morais-Cabral J.H.,
Dissecting the Molecular Mechanism of Nucleotide-Dependent Activation of the KtrAB K+ Transporter. PLoS Biology14(1):, 2016. [Journal: Article] [CI: 11] [IF: 9,8]
DOI: 10.1371/journal.pbio.1002356 SCOPUS: 84961353773. PLoS Biology. 2016

Marques-Carvalho M.J., Oppermann J., Muñoz E., Fernandes A.S., Gabant G., Cadene M., Heinemann S.H., Schönherr R., Morais-Cabral J.H.,
Molecular Insights into the Mechanism of Calmodulin Inhibition of the EAG1 Potassium Channel. Structure24(10):1742-1754, 2016. [Journal: Article] [CI: 7] [IF: 4,9]
DOI: 10.1016/j.str.2016.07.020 SCOPUS: 84989908805. Structure. 2016

Harley C.A., Starek G., Jones D.K., Fernandes A.S., Robertson G.A., Morais-Cabral J.H.,
Enhancement of hERG channel activity by scFv antibody fragments targeted to the PAS domain. Proceedings of the National Academy of Sciences of the United States of America113(35):9916-9921, 2016. [Journal: Article] [CI: 8] [IF: 9,7]
DOI: 10.1073/pnas.1601116113 SCOPUS: 84984876913. Proceedings of the National Academy of Sciences of the United States of America. 2016

Fernandes A.S., Morais-Cabral J.H., Harley C.A.,
Screening for Non-Pore-Binding Modulators of EAG K+ Channels. Journal of Biomolecular Screening21(7):758-765, 2016. [Journal: Article] [CI: 3] [IF: 2,4]
DOI: 10.1177/1087057116636592 SCOPUS: 84979221631. Journal of Biomolecular Screening. 2016

Morais-Cabral J.H., Robertson G.A.,
The enigmatic cytoplasmic regions of KCNH channels. Journal of Molecular Biology427(1):67-76, 2015. [Journal: Review] [CI: 27] [IF: 4,5]
DOI: 10.1016/j.jmb.2014.08.008 SCOPUS: 84919618793. Journal of Molecular Biology. 2015

Pessoa J., Fonseca F., Furini S., Morais-Cabral J.H.,
Determinants of ligand selectivity in a cyclic nucleotide-regulated potassium channel. Journal of General Physiology144(1):41-54, 2014. [Journal: Article] [CI: 4] [IF: 4,8]
DOI: 10.1085/jgp.201311145 SCOPUS: 84903790332. Journal of General Physiology. 2014

Vieira-Pires R.S., Szollosi A., Morais-Cabral J.H.,
The structure of the KtrAB potassium transporter. Nature496(7445):323-328, 2013. [Journal: Article] [CI: 68] [IF: 42,4]
DOI: 10.1038/nature12055 SCOPUS: 84876273276. Nature. 2013

Adaixo R., Harley C.A., Castro-Rodrigues A.F., Morais-Cabral J.H.,
Structural Properties of PAS Domains from the KCNH Potassium Channels. PLoS ONE8(3):, 2013. [Journal: Article] [CI: 35] [IF: 3,5]
DOI: 10.1371/journal.pone.0059265 SCOPUS: 84875019376. PLoS ONE. 2013

Mari S.A., Pessoa J., Altieri S., Hensen U., Thomas L., Morais-Cabral J.H., Muller D.J.,
Gating of the MlotiK1 potassium channel involves large rearrangements of the cyclic nucleotide-binding domains. Proceedings of the National Academy of Sciences of the United States of America108(51):20802-20807, 2011. [Journal: Article] [CI: 43] [IF: 9,7]
DOI: 10.1073/pnas.1111149108 SCOPUS: 84855517288. Proceedings of the National Academy of Sciences of the United States of America. 2011