Determining structural features of a collagen lysyl hydroxylase that promotes lung cancer metastasis

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Project Summary/Abstract: Candidate: Dr. Guo has received broad training in biochemistry and structural biology. He is a postdoctoral fellow at MD Anderson Cancer Center seeking to understand how collagen lysyl hydroxylase (LH) structural features regulate lung cancer metastasis. Dr. Guo is a highly productive investigator, with 18 peer-reviewed papers (6 of which as first or co-first author). As recognition of his achievements, he received numerous awards during his doctoral and postdoctoral training. Career Development/Training: Dr. Guo's mentors at MD Anderson include Dr. Jonathan Kurie, a physician- scientist with expertise in lung cancer biology and mouse modeling of human lung cancer, and Dr. John Tainer, a renowned protein crystallographer studying macromolecular assemblies to inform drug design. Additionally, Dr. Guo will receive training from Dr. Mitsuo Yamauchi (UNC-Chapel Hill), a collagen biochemist who was among the first to elucidate how collagens are modified by LHs. These investigators have designed a training program centered on their key scientific disciplines that will strengthen Dr. Guo's abilities in their respective fields and provide the skills needed for a smooth transition to independence. Research: Our group has shown that high expression of LH2 drives lung cancer metastasis and induces a collagen cross-link switch in tumor stroma. LH2 is a therapeutic target of interest, but selective LH inhibitors are not available, a deficiency due in part to a lack of structural insight into LH2. The objective of my proposal is to elucidate LH2 structural features that promote lung cancer metastasis. In my preliminary results, I describe new methods to produce human LH2 protein and assay its activity and the structure of the catalytic domain of a viral LH homologue, which revealed a homodimer stabilized by Fe+2-binding. I found that the two active sites flank a deep surface cleft on the dimer interface, suggesting that dimerization creates a collagen- binding site, and that basic residues adjacent to the active site are positioned to form salt bridges with telopeptidyl acidic residues on collagen. From these findings, I hypothesize that LH2 has telopeptidyl-LH activity owing to unique features that allow it to form Fe2+-stabilized dimeric structures that interact with telopeptidyl lysines on collagen. I will test this hypothesis by determining how LH dimer assemblies are stabilized by Fe2+-binding and interact with telopeptidyl lysine residues to regulate collagen cross-link formation and lung tumorigenesis. In sum, my proposal will address the clinical problem of lung cancer metastasis. The novelty rests in preliminary results that provide the first structural insights into a collagen LH, hypotheses that challenge current paradigms, and technologies that facilitate quantification of LH enzymatic activity and evaluation of candidate metastasis drivers.