Metal ions as modulators of folding and amyloidogenic pathways in the S100 protein family

ITQB PhD Seminars

Title: Metal ions as modulators of folding and amyloidogenic pathways in the S100 protein family

Speaker: Hugo Botelho

Laboratory: Protein Biochemistry Folding & Stability

Abstract

Metal ions such as calcium or zinc are important second messengers, transducing upstream signaling events into protein activation by binding to specific sites, frequently promoting protein conformational changes. A major part of calcium signal buffering/transducing in vertebrates is carried out by proteins of the S100 family. They are activated upon calcium binding, which triggers a conformational change exposing a protein docking site. Some family members also bind zinc, copper or magnesium, which occasionally enhance or repress the calcium signaling or modulate the conformational stability.
We have analyzed the conformation and stability changes brought about in some S100 proteins by different metallation states. In S100A2, a tumor suppressor under the control of calcium and zinc acting through binding to p53 in a metal-dependent manner, we have examined the effect of selective binding of these metal ions by using zinc binding site mutants. By combining the analysis of secondary structure and the assessment of the conformational stability of the S100A2 mutants in different metallation states (apo, Zn2+ and Ca2+) we have obtained evidence for a synergistic effect between metal binding, protein stability and S100A2 activity, according to which Ca2+ activates and stabilizes the protein, the opposite being observed upon Zn2+ binding. More recently, we have examined the amyloidogenic potential of the S100 proteins. Some family members have been found to form amyloid inclusions in prostate cancer patients and our preliminary results indicate that the amyloid-forming potential may be shared by other homologs and be metallation state dependent.

Short CV
2006: Degree in Biochemistry by the Faculdade de Ciências da Universidade de Lisboa
2005-2006: Undergraduate research student at the Protein Biochemistry, Folding and Stability Group, ITQB, under the supervision of Dr. Cláudio Gomes
Since 2006: PhD student at the Protein Biochemistry, Folding and Stability Group, ITQB, under the supervision of Dr. Cláudio Gomes