The main theme of mechanosensitive ion channel research in the Phillips Group is aimed at understanding two general classes of problems.
1) Mechanosensitivity by itself is a general term to describe how cells respond to changes in their mechanical environment – from physical touch on the plasma membrane by external objects or the polymerization of actin, to osmotic stresses in the environment. Our group has focused on a well characterized mechanosensitive protein known as the Mechanosensitive Channel of Large Conductance (MscL), found in the plasma membrane of E. coli (and other bacteria). This protein is responsible for managing the mechanical stresses present during osmotic down-shock. MscL senses the tension in the membrane and changes to an open conformation to release osmolytes and water, thereby equilibrating the otherwise lethal osmotic pressure gradient.
But how does MscL sense tension in the membrane? How do the elastic properties of the surrounding lipids affect the function of the channel? For that matter, how do the elastic properties of the lipids affect the function of any channel or transmembrane protein? In a continuum elastic model, the bilayer can affect proteins through its bending stiffness, resistance to area dilation, resistance to compression, and its hydrophobic thickness. We find that hydrophobic mismatch, most strongly related to compression deformations, has a severe effect on the function of MscL. Indeed, other experimental work has shown this qualitatively. We are moving towards a detailed electrophysiological study of the interplay between membrane tension and the mismatch between the hydrophobic regions of the protein and the bilayer.
Figure 1. Hydrophobic mismatch and a protein’s shape deform the surrounding bilayer in a quantifiable way. Here, a protein induces hydrophobic mismatch, midplane bending and leaflet bending – all of which can be translated into forces which the protein must resist. However, these forces can have profound effects on the energetics of conformation.
2) Our understanding of the bilayer deformations which surround transmembrane proteins led us to wonder if there could be communication between neighboring proteins that is mediated strictly by the elastic nature of the bilayer. We found that the finite decay length of the elastic deformations around a transmembrane protein lead to interactions between neighboring proteins. In fact, these so-called elastic interactions tend to couple the conformational states of proteins in proximity, and lead to conformationally dependent spatial organization within the membrane. With some knowledge of the open and closed structures of MscL, we calculated how two such proteins embedded in a bilayer, able to otherwise freely diffuse, will communicate their conformational state via the bilayer, leading to cooperative channel gating. Additionally, the interactions are often attractive, and hence lead to spatial dimerization that is heavily dependent on the proteins’ conformations.
Figure 2. Deformations in the bilayer surrounding two transmembrane proteins lead to elastic interactions, capable of communicating information about conformational state and spatially organizing the proteins. a) The interaction between two closed MscL channels. b) The interaction between an open and a closed MscL channel. c) The interaction between two open MscL channels.
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I was born in California in the summer of 1976. Raised by loving parents who encouraged me in my creative endeavors, I grew up in a good school district in Castro Valley, (in the East Bay Area). One of my earliest memories is taking apart a vacuum cleaner to see how all the parts fit together. I also used to stack rocks and sticks into interesting little inventions when I was in elementary school.
Growing up I spent a lot of time hanging out in my local arcade with my brother Andy, playing video games until we beat them. Pinball machines were the best place for finding tokens that would get stuck on the sides of the coin-return slots.
During my freshman year in high school I participated in a one-year weaving and textile arts apprenticeship program under Lolli Jacobsen at the Mendocino Art Center. My main focus was weaving. I also took classes in spinning, dying, surface design, felting and other textile arts. During this time I also attended Mendocino High School where I kept up with my class by taking a minimum load of 3 classes.
The remainder of my high school career went by without too much drama. I attended Principia Upper School, graduating in 1994. I participated in varsity soccer and graduated with honors near the top of my class.
I then went on to attend Principia College, where I majored in Studio Art. I began learning web design at night on my own while I was a student. My senior year I was selected to be the Editor in Chief of the Sheaf, Principia’s student yearbook publication. We created a special centennial year edition of the Sheaf, including a custom coded CD-ROM. The yearbook went on to win the 1998 Associated College Press Pacemaker award, the highest honor a university yearbook can win. I graduated Cum Laude with a B.A. in Studio Art in June of 1998 and was immediately hired by Principia to help them work on their website.
After working on Principia’s website for a year and a half, I was hired by a company called GlobalStreams, a small St. Louis-based startup that was involved with streaming audio. I had done some freelance work for them previously, and once they got some funding they made an offer that I couldn’t refuse. My job for GlobalStreams included building website pages, user interface designs, and a serious amount of hard-core Flash coding.
GlobalStreams went through a series of transitions and ownership / investor changes over the years. Eventually they were bought by another company called Play Streaming Media Group, which promptly changed their name to GlobalStreams. That company then went on to rebrand itself as Vibe Solutions Group. At Vibe Solutions Group I was the primary user interface designer, and built product logos and user interface designs for their whole lineup of products, including Video Mail, Video Caller, Vibe Journal and Pyro.TV.
In May of 2006 I left Vibe Solutions Group to pursue a new small startup Katanaa with a couple of friends, building custom web applications for a variety of clients. During this time, we built a number of very cool programs, including a case study assigner system built to the specifications of one of the most popular and exclusive business schools. We also built a system for keeping track of your online training and fitness stats (Collabofit) that proved to be popular for a while, until another application that I was developing (RSS2.com) ended up eating too many server resources and the server got slow.
Currently I am running my business (Serafini Studios) and do work for a variety of clients, large and small, including:
Feel free to get in touch if you have a project that you think I’d be interested in.
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My hobbies include taking pictures (most of which end up on Flickr) and working to maintain a top 10 Google ranking for “Gabriel” (out of 102 million other “Gabriel” results out there). I really enjoy crewing on racing sailboats on the San Francisco Bay.
Blood type: A positive
Chinese Zodiac: Fire Dragon
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