Research
E.E. Cummings once wrote that he was “abnormally fond of that precision which creates movement”. While he was thinking about how word arrangements and sentence structure can be organized for effect in poems, he was right that for something to have life, it needs to move.
The accomplishment of whole cellular movement and intracellular motility requires extreme precision, specifically, the precise spatiotemporal control of processes at the molecular scale. We study how the regulation of the actin cytoskeleton, a self-organizing macromolecule and its binding proteins, leads to the emergent phenomenon of motility. We use a combination of microscopy, molecular techniques, and computational approaches to elucidate function across length scales from molecules to cells.
Why motion?
Life is an interconnected series of dynamic, emergent processes, each greater than the sum of its parts. Cellular motility is a highly complex coordination of non-equilibrium processes not wholly controlled by any singular protein, macromolecular complex, or system. The cells in our body move during wound healing, cancer metastasis, and embryonic development. In tissues with high turnover such as the intestinal epithelium or the epidermal skin layer, differentiated cells actively migrate to where they are needed post-division. Unicellular free-living protists such as amoebae also move to explore their environment, find food, and escape predation. Motility is thus both an intrinsic behavior and the functional output of various information processes. Yet how it emerges from the sum of these local processes is an open question. Life is so fascinating to study in large part due to the diversity in solutions generated in solving complex biological problems—and motility is certainly no exception. Cells construct a variety of motility apparatus from the complex macromolecular machinery of the flagellar motor to dendritic actin networks. While the flagellar motor is a self-assembled rotary engine, dendritic actin networks are dynamically assembled, self-organizing, force-generating distributive molecular motors formed from the coordinated assembly of actin filaments that push on membranes.
beryl rappaport
david bulkley
Actin network assembly: While actin monomers can spontaneously form filaments upon addition of ATP and salt, in a cell, actin polymerization is tightly controlled and regulated by hundreds of binding proteins. Polymerases like nucleation promoting factors for the Arp2/3 complex dictate where and when actin assembles. These proteins share a conserved domain structure with high homology regions for binding both naked actin monomers and monomers bound to profilin. We are interested in how minor differences in this domain structure can tune actin network architecture and dynamics.
Intracellular membrane dynamics: How does actin maintain and organize organellar membranes? Organelles such as mitochondria are dynamic, constantly assembling and disassembling. We investigate how actin polymerization contributes to dynamics on both the cytoplasmic face and lumenal/matrix-facing side of the membrane.
Amoeboid motility: Across length scales from proteins to mammals, form is related to function. Amoeboid motility is a type of motion named for a constant change in shape. Both free-living single-cell protists and human cells utilize this type of motility, driven alternately by cytoplasmic pressure or the force of actin polymerization. We investigate the crawling motility of both unicellular and metazoan cells and how the actin cytoskeleton drives their movement.