Page 5 - Annual Report 2020

Primary Research Areas:
1) Membrane transport processes
2) Peroxisome biogenesis and homeostasis
3) Lipid/protein interactions
4) Lipid and fatty acid metabolism
The Hormel Institute ranks among a handful of elite institutions housing a Titan Krios microscope combined with a direct electron detector, a setup designed to obtain near-atomic resolution (routine- ly achieving better than 0.5 nanometer resolu- tion). This allows for accurate visualization of the molecular details underlying the functioning of macromolecules and has revolutionized structural biology and allowed for targeting of complex biological problems previously considered off- limits to high resolution visualization. Such insight is invaluable in obtaining molecular details of membrane protein interactions with drugs, trans- port substrates, and inhibitors and can aid in the design of novel therapeutics targeting diseases stemming from membrane protein dysfunction.
Over the last year since its inception, our lab has determined the cryo-EM structures of several human membrane transporters at near atomic resolutions. Along with their biochemical charac- terization, these new structures will be part of sev- eral upcoming publications we are in the process of preparing. We have added a new postdoc to
our roster, Dr. Le Thi My Le, who also successfully applied for and is partially funded by the 2020 Eagles Postdoctoral fellowship award. We have co-authored two recent publications with a fellow Hormel Institute collaborator, Dr. Rick Brown (Gao et al, Anal Chem, 2020), as well with Dr. Alam’s postdoctoral lab on the structure of human ABCB4 / MDR3 (Olsen et al, NSMB 2020). Finally, Dr. Alam
Figure 1: Demonstrating the power of cryo-EM. The first structure of a human A family ABC transporter embedded in a lipid bilayer (left). The dashed oval highlights a patch of ordered lipids traversing the space between the two halves of the transporter. Our data allow us to formulate
a mechanism (right panel) for the ABC transporter mediated lipid loading of apolipoproteins.
was awarded a research grant from the United Leukodystrophy Foundation to support his work on peroxisomal biogenesis and dysfunction.
The Alam lab has made significant progress in deciphering the molecular details that govern
lipid metabolism and homeostasis by studying the detailed 3D structures of an important class of membrane proteins called ABC transporters. Specifically, the Alam lab has determined the high-resolution structures of ABC transporters involved in the movement of cholesterol and phos- pholipids across cellular membranes, revealing hitherto unseen details about how this essential step in formation of high density lipoprotein (HDL) particles form and how their dysfunction leads
to a range maladies ranging from various brain disorders including Alzheimer’s disease, to various neurodegenerative diseases, as well as cancer.
The Alam lab uses a combination of biochemistry, cell biology, and state of the art Cryo-EM tools to study this group of human proteins that has for decades proven extremely difficult to study.
Research Specialties:
1) Membrane protein biochemistry
2) Cryo electron microscopy
3) X-ray crystallography
Lab Personnel:
Dr. Le Thi My Le (Postdoctoral researcher, Nov 2019 – present)
Dr. James Thompson (Senior Scientist/ researcher V, Jun 2019-present)
Mehedi Hasan (Technician/Researcher 1, Jun 2019 – July 2020)
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