On January 21st, 2016, we will hold the first meeting of the BTDD project in Europe. The meeting will have two parts – the first is a Mini Workshop hosted by the CRC 1093 at the University of Duisburg-Essen (see agenda below). This Mini Workshop is open to all scientists and the general public. The second part is a closed meeting for participating scientists only. We are grateful to CRC 1093 for their hospitality and look forward to a stimulating and vibrant meeting.
We don’t usually think of cancer as a disease related to amyloid or to protein aggregation. In cancer, the control systems that dictate the cell life cycle are lost and cells begin to proliferate out of control. A key element in the control system is the “tumor suppressor” protein, p53. p53 has been described as “the guardian of the genome” because it protects genes from mutation. However, the gene encoding p53 can be mutated itself, leading to formation of a dysfunctional protein, loss of control, and cancer.
An interesting recent discovery is that a sub-group of the mutations lead to protein aggregation, similar to what happens in amyloidoses, such as Alzheimer’s or Parkinson’s diseases. This finding is highly important because p53 acts as a homotetramer (a protein complex made of four identical subunits) and to be functional, each one of the four subunits has to have the correct structure. If just one is mutated, the complex falls apart. Because our genome has two copies of each gene, if a structure-altering mutation occurs in one of the copies and that mutation leads to a dysfunctional protein, 50% of the protein produced will be dysfunctional. But when four intact copies are needed for the protein to function and one copy of the gene is mutated, only 1/16, or 6.25%, of the tetramers will be normal and functional.
The problem with amyloid formation is that the normal protein tends to co-aggregate with the bad one, reducing the percentage of available normal protein even more. And if that is not bad enough, protein “cousins” of p53, called p63 and p73, also co-aggregate with the mutant protein, reducing the cells ability to control its processes even more. Moreover, the aggregates can be transmitted to other cells and induce abnormal aggregation in them, a possible mechanism for the propagation of cancer.
In addition to the loss of control, the rogue protein aggregates themselves are cytotoxic, similarly to protein aggregates in other amyloidoses. This is where the molecular tweezer, CLR01, might help. CLR01 is known to alter the formation of the toxic aggregates and facilitate their degradation by the body’s clearance mechanisms. Can it do that with mutant p53? Facilitate clearance of the mutant protein and possibly release the good protein? To begin to answer these questions, the team of Dr. Danny Segal at Tel Aviv University examined the effect of CLR01 on two prevalent mutant forms of p53 in a series of biophysical and biochemical tests. They found that CLR01 stabilized intermediate-size aggregates of the mutant proteins. Thus, the transition from small oligomers to the intermediate-size aggregates was accelerated, but further aggregation was inhibited when the mutant proteins interacted with CLR01.
These observations led to an important question: are the intermediate aggregates still toxic to cells? When the researchers added the aggregates of mutant p53 itself, without CLR01, to cultured cells, the cells died, but when they added the mixture of mutant p53 with CLR01, the molecular tweezer protected the cells and they survived. These findings suggest that CLR01 may be helpful in cases of cancer caused by p53 mutations because it may help prevent both the formation of toxic protein aggregates and the co-aggregation of healthy protein with the mutated form.
The study was published in the American Chemical Society journal Biochemistry.
Diabetes is known as a disease of uncontrolled blood-sugar levels because the body does not produce enough insulin, or the insulin that is produced is not used effectively by the body. Most people are not aware that type-2 diabetes is also the most prevalent amyloidosis. In type-2 diabetes, a small protein called Islet Amyloid PolyPeptide (IAPP) forms toxic aggregates that kill the insulin-producing beta cells in the pancreas.
A new study now shows that the molecular tweezer, CLR01, prevents the aggregation of IAPP and its toxicity towards pancreatic cells. The study, which is published in the American Chemical Society (ACS) journal ACS Chemical Biology, shows how CLR01 binds to IAPP, changes its structure, and prevents its aggregation. The study also shows that the blood levels of CLR01 needed for therapeutic effect can be achieved without causing safety concerns.
The new study was led by Gal Bitan‘s group at UCLA in collaboration with Thomas Schrader and Frank Klärner, University of Duisburg-Essen, Elsa Sanches-Garcia, Max-Planck-Institut für Kohlenforschung in Mülheim, and Chunyu Wang, Rensselaer Polytechnic Institute.
Our newest research paper, entitled “Amyloid β-Protein Assembly: The Effect of Molecular Tweezers CLR01 and CLR03“, was selected as the American Chemical Society (ACS) Editors’ Choice for March 27, 2015.
The paper describes a detailed investigation of the interaction of amyloid β-protein (Aβ), the protein believed to cause Alzheimer’s disease, with the molecular tweezer, CLR01, and the negative-control derivative CLR03. Previously, CLR01 was found to be an effective inhibitor of Aβ aggregation and toxicity in test-tube experiments, cell culture, and animal models. The new study showed that upon interaction with Aβ, CLR01 reduces the concentration of specific structures and essentially eliminates structures believed to be particularly harmful, which are made of 6 and 12 units of Aβ.
The study was conducted primarily by Xueyun Zheng, a graduate student in the group of Professor Michael Bowers at the University of California, Santa Barbara, and was published in the Journal of Physical Chemistry B.
ACS Editor’s Choice articles are selected from among the over 60 publications of the ACS. With ACS Editors’ Choice, ACS offers free public access to new research of importance to the global scientific community. These peer-reviewed, open access articles consist of research that exemplifies the Society’s commitment to improving people’s lives through the transforming power of chemistry. The selection of these articles is based on recommendations by the scientific editors of ACS journals from around the world. To date, only 7 papers from the Journal of Physical Chemistry B received this honor.