DisciplinaGênese e Desenvolvimento de Células e Tecidos61 materiais • 70 seguidores
Exemplos de distúrbios associados a erros de dobramento das cadeias polipeptícas (Fragmentos do texto da página de FAQ do site http://folding.stanford.edu) What happens if proteins don't fold correctly? Diseases such as Alzheimer's disease, Huntington's disease, cystic fibrosis, BSE (Mad Cow disease), an inherited form of emphysema, and even many cancers are believed to result from protein misfolding. When proteins misfold, they can clump together ("aggregate"). These clumps can often gather in the brain, where they are believed to cause the symptoms of Mad Cow or Alzheimer's disease. (\u2026) Alzheimer's Disease (AD) Huntington's Disease (HD) AD is caused by the aggregation of relatively small (42 amino acid) proteins, called Abeta peptides. These proteins form aggregates which even in small clumps appear to be toxic to neurons and cause neuronal cell death involved in Alzheimer's Disease and the horrible neurodegenerative consequences. HD is caused by the aggregation of a different type of proteins. Some proteins have a repeat of a single amino acid (glutamine, often abbreviated as "Q"). These poly-Q repeats, if long enough, form aggregates which cause HD. We are studying the structure of poly-Q aggregates as well as predicting the pathway by which they form. Similar to AD, these HD studies, if successful, would be useful for rational drug design approaches as well as further insight into how HD aggregates form kinetically (hopefully paving the way for a method to stop the HD aggregate formation). Cancer and P53 Half of all known cancers involve some mutation in p53, the so-called guardian of the cell. P53 is a tumor suppressor which signals for cell death if their DNA gets damaged. If these cells didn't die, their damaged DNA would lead to the strange and unusual growths found in cancer tumors and this growth would continue unchecked, until death. When p53 breaks down and does not fold correctly (or even perhaps if it doesn't fold quickly enough), then DNA damage goes unchecked and one can get cancer. We have been studying specific domains of p53 in order to predict mutations relevant in cancer and to study known cancer related mutants. Osteogensis imperfecta In collaboration with other groups at Stanford (especially Dr. Teri Klein's group at Stanford University Medical Center), we are looking at Collagen folding and misfolding. Collagen is the most common protein in the body and mutations in collagen leads to a very nasty disease called Osteogenesis Imperfecta (or OI for short). In many cases, OI is lethal and leads to miscarriage. However, 1 in 10,000 people have some sort of mutational in collagen. For many, where the mutation is not very serious, it lies unknown and misdiagnosed and leads to brittle bones and other more subtle problems. In others, however, mutations lead to more serious morphological disorders (as shown on the right). Parkinson's Disease (PD) We have also performed preliminary studies on a key protein implicated in Parkinson's disease. Alpha-synuclein is a natively unfolded protein and its folding/misfolding (see figure on the right for misfolded aggregates) appears to be critically linked to PD. We are evaluating the application of various FAH methods to this problem. Antibiotics The Ribosome is an amazing molecular machine and plays a critical role in biology, as it is the machine that synthesizes proteins. Because of this critical role, and some small but fundamental differences in the ribosomes of mammals and bacteria, the ribosome is the target for about half of all known antibiotics. These antibiotics typically work by preventing bacterial ribosomes from making new proteins, thus killing them. We have several projects on going to study the ribosome. Since the ribosome is so huge, these WUs are big WUs and have required us to push the state of the art of FAH calculations. However, with these new bigWUs, FAH is set up to study more and more complex problems, and if successful, with greater and greater biomedical impact.