Page 48 - Hormel Report 2021

Anna Sundborger-Lunna, Ph.D.
“By revealing how mitochondrial cell death is controlled in healthy cells, we will be able to manipulate and activate this process in
cancer cells.”
Anna Sundborger-Lunna
48 | THE HORMEL INSTITUTE // Cryo-EM and
Molecular Cell Biology
SECTION LEADER / ASSISTANT PROFESSOR
UNIVERSITY OF MINNESOTA
In the Cryo-EM and Molecular Cell Biology Section we are studying how membrane- remodeling proteins assemble into large
complexes and regulate fundamental cell events, such as apoptosis, autophagy and mitochondrial dynamics. Several molecular players with membrane-remodeling activity have been implicated in mitochondrial dynamics: (i) endophilin B1, a potential tumor suppressor involved in a multitude of intracel- lular membrane trafficking events (Fig. 1); (ii) dynamin family member Drp1, which is required for fission of the mitochondrial outer membrane (MOM); (ii) Immunity-Related GTPase M (IRGM), an GTPase related to the dynamin super
family critical for autophagy during the innate response to intracellular pathogens; and (iii) Bax, a pro-apoptotic protein that trans-locates to the mitochondria where it is activated to form pores in the MOM, leading to the release of cytochrome c and subsequently, apoptosis.
Figure 1. Molecular mechanisms of endophilin B1-mediated membrane remodeling. In the cytosol, H0 adopts an extended organization that interacts with the SH3 domain to form an “in- tra-molecular clamp”. Interactions with binding partners, such as proline-rich domain containing protein dynamin 2 displaces the SH3 domain and releases the clamp on the BAR domain, enabling membrane remodeling activity. This activation is also propagated or simultaneously initiated by local membrane properties, such as specific lipid composition or inherent curvature. Following the release of the SH3 clamp, H0 becomes helical and wedges into the lipid bilayer, which is further augmented by H1i. This regulates the scaffolding activity of the BAR domain, which imposes its inherent curvature onto the membrane via electrostatic interactions. Continuous recruit- ment of “activated” endophilin B1 dimers results in end-to-end assembly, which promotes curvature and causes membrane tubulation. 5) Following down-stream membrane remodeling events, such as dynamin-mediated fission, endophilin B1 is released from the membrane and returns to its auto-inhibited state in the cytosol.