Research over the past decade has uncovered the physiological importance and disease relevance of a large membrane transporter/receptor superfamily, called the MtN3 clan. For example, SWEET transporters are critical for sugar efflux and utilization; PQ-loop transporters have been linked to cystinosis and Batten disease; the mitochondrial pyruvate carrier controls a critical branch point of the central metabolic pathway and is implicated in cancer; and KDEL receptors are crucial for endoplasmic reticulum quality control and have been associated with dilated cardiomyopathy. Despite these diverse and important functions, we still know little about the molecular mechanisms of MtN3 transporters. Our overall objective is to provide structural and mechanistic insights that elucidate the physical basis of cross-membrane transport and shed light on the physiological functions and disease-causing malfunctions of MtN3 transporters. We will focus on SWEET sugar transporters, the founding members of the MtN3 family, and then expand our work to include related transporter families. In our prior research, we solved the first eukaryotic SWEET structure in an inward-open state and high-resolution structures of bacterial SemiSWEETS in multiple conformation states, shedding light on sugar transport by SWEETs and the alternating access mechanism more broadly. These results provide a solid foundation to further probe the mechanisms of MtN3 transporters. In this renewal application, we propose to extend this work to: (1) elucidate the structural basis of crosstalk and alternating access of eukaryotic SWEET; (2) dissect the substrate selectivity of SWEET transporters; and (3) determine the structural basis of the PQ-loop transporter. Understanding how MtN3 transporters work at the molecular level will provide rich insights into their transport mechanisms and crosstalk. Moreover, this work will provide a blueprint to understand the function of PQ-loop transporters and unravel the mechanisms underlying devasting lysosomal storage diseases. Ultimately, our work will produce essential knowledge that will facilitate targeting MtN3s for therapeutics. !

Public Health Relevance

SWEETs are novel sugar transporters and prototypic members of the MtN3 membrane protein family, which has important physiological functions and disease relevance. The goal of this project is to determine how SWEETs and related MtN3 transporters work at the molecular level. The results of the project will produce essential knowledge to target MtN3s for therapeutics for diseases such as lysosomal storage disease, cancer, and diabetes.!

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Biochemistry and Biophysics of Membranes Study Section (BBM)
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Bond, Michelle Rueffer
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Stanford University
Schools of Medicine
United States
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Latorraca, Naomi R; Fastman, Nathan M; Venkatakrishnan, A J et al. (2017) Mechanism of Substrate Translocation in an Alternating Access Transporter. Cell 169:96-107.e12
Tao, Yuyong; Cheung, Lily S; Li, Shuo et al. (2015) Structure of a eukaryotic SWEET transporter in a homotrimeric complex. Nature 527:259-263