Hughes Mentor:  Brian Crane

Department: Chemistry and Chemical Biology

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Meet a Cornell Researcher!

Dr. Brian Crane is an Associate Professor in the Department of Chemistry here at Cornell University. He graduated with a bachelor of science from the University of Manitoba in Canada in 1990, and attained his Ph.D. from the Scripps Research Institute in 1996. His decision to come to Cornell was inspired by a number of factors, including location, strength of the chemistry department, as well as specifics of the university’s offer.

One focus of Dr. Crane’s research is the chemistry that allows organisms to monitor energy in their environment. This biophysical sensing is applicable to many systems, ranging from bacterial chemotaxis (movement of bacteria as influenced by chemicals in their environment) to the mammalian circadian rhythm. In other words, he is interested in the precise biophysics and biochemistry responsible for the effect of the human body clock with which we are all familiar. He goes about studying this problem using a variety of complex techniques. One of these techniques is known as x-ray crystallography. Generally, this technique involves the directing of x-rays through crystals of proteins, and the determination of protein structure based on the diffraction pattern of the x-rays. Crystallography can be a very challenging field and requires the very difficult processes of growing crystals and later, interpreting data. Dr. Crane takes this process one step further, mapping structural changes of light-sensing proteins following exposure of the protein crystals to laser beams. Based on his data, and the findings from collaborators with more molecular biology-oriented laboratories, he has devised a number of impressive models that can explain the light-sensing properties of proteins, and the subsequent transmission of this signal within organisms such as bacteria or humans.

Dr. Crane currently has two undergraduate students conducting research in his laboratory, which is located in the Olin Laboratory building. The most important qualities he demands of undergraduates are effort and motivation. When not conducting research, he enjoys spending time with his family. Dr. Crane was very helpful in giving the time to describe and discuss his intriguing research, and is one of the many dedicated members of the Cornell faculty.

Dr. Crane

Dr. Crane is from Canada and received his undergraduate degree from the University of Manitoba in 1990. He obtained his PhD from the Scripps Research Institute in 1996. He always had a strong passion for the sciences and after his undergraduate years decided that research was his forte. He came to Cornell because of its strong foundations in physical and biological sciences. He liked the environment and the resources that were available to him at Cornell. He is also very keen on teaching undergraduates and that made the difference for his choosing Cornell over other medical institutes. When he is not doing research, he is having fun with his family. He coaches his son’s hockey team and says he loves the Ithaca community.

Dr. Crane’s research is in the field of physical biochemistry. His group is trying to analyze how various proteins involved in signal transduction are able to interact with other proteins, electrons and photons. All organisms are able to sense and act to various stimuli in the environment. Dr. Crane’s research looks at the biophysical mechanisms that are involved in these pathways. Specifically, his research focuses on understanding the molecular mechanisms of bacterial chemotaxis and circadian clocks in fly and fungi (Neurospora). In these organisms, light or reducing agents activate certain cofactors within sensory proteins. This captured energy is used to produce new interactions among response proteins within the cell.

Circadian rhythms are very important in all organisms because they help to anticipate environmental stimuli. All cells have ‘clocks’ and there are many ‘clock’ proteins that aid in complex and interconnected signaling pathways. ‘Clock’ proteins are very important and any mutations in them could lead to tumors and disruptions to the cell cycle. Dr. Crane’s group is trying to analyze the interactions that occur between these sensory complexes by studying model organisms such as the fungal Neurospora. In this model, light activates certain white color complexes (WC) within the nucleus of cells. These transcribing factors are then switched on and begin transcription of genes crucial in many signaling pathways. The increase in expression of these products then inhibits the WC complexes – in essence a feedback inhibition. There are 2 WC complexes – WC1 and WC2. Another protein, VVD, also plays a crucial role by inhibiting WC-1 in response to light. This leads to pulses of activity and a sinusoidal oscillation in the response system of the transcription factors. This is very efficient because the entire system need not be turned on continuously. It has also been shown that WC-complexes respond to redox changes as well. These sensory complexes and proteins are active even in the dark. Thus, both light and redox agents work together to activate the signaling pathways. Dr. Crane’s group hypothesize that VVD may well act as a competitive inhibitor to WC-2. This is because in the absence of VVD the pathway is turned on and a steady signal is received rather than oscillations. WC-2 could have a binding site that either VVD or WC-1 interacts with. This competition could account for the pulses and oscillations of light energy. Flavin cofactors within these sensory proteins are key players in this signaling pathway. Using X-ray crystallography, Dr. Crane’s group has shown structural conformational changes in the protein during these interactions. A very important adduct is formed on a series of biochemical reactions that eventually leads to the reduction of the cofactor FAD.

Flies have a similar protein – cryptochrome which consists of a dimer. In this system, the protein degrades or inhibits the activity of proteins that transcribe genes to activate the light sensing pathway. Thus, it is more of a negative control than in the fungal system. Both systems share the same flavin cofactor. However, in this model no adduct is formed; rather the protein pulls off an electron to form the reduced state. Thus, reduction of FAD is very important in both model systems.

Dr. Crane’s research also centers on understanding the molecular mechanisms of chemotaxis in bacteria. Bacteria like E.Coli are very sensitive to various metabolites, nutrients and toxins. They use a concentration gradient to orient themselves away or towards the stimuli. They use their flagella motor to propel themselves. They have 2 modes of motion – a clockwise motion that causes them to re direct themselves – a process referred to as a ‘tumble’ and a counter-clockwise motion that causes all the flagella to line up and propels the organism in a particular direction – a smooth motion. Various kinases and receptors are important in this movement pathway. Sensory receptors on the outer membrane are activated by binding of certain sugars or amino acids. AER protein is a sensory protein on the inside of the cell that senses electrons passing through the cell membranes. This activates a kinase cheA which phosphorylates cheY a response regulator. This in turn controls the flagella motor filament. This entire process is known as the excitation phase. Dr. Crane uses X-ray crystallography to monitor structure of proteins and look at any conformational changes during the interactions. His lab also employs electron spin resonance spectroscopy which can measure electrons in complexes to determine the distances between complexes during interactions. Ultimately, his lab has generated a model for the various kinase-receptor complexes – a lattice model allowing for lateral interactions of various kinases. These involve many couplings of kinases to various receptors. Thus, large scale rearrangements in the entire system are thought to occur. His lab is currently trying to test the lattice model.