Protein for all times

The institute's scientists were able to observe in real time structural changes that occur in a protein molecule within milliseconds

Dr. Dan Toufik. Adaptability

Legend has it that Napoleon Bonaparte, among all his other unique qualities, was able to perform three tasks at once. Normal humans, on the other hand, have trouble doing two tasks at once. Indeed, as far as protein molecules are concerned, the prevailing opinion among scientists, for years, is that each such molecule is competent and capable of performing only one specific action. But, nevertheless, over the years, the question came up again and again, is it possible that any protein molecule is capable of performing a variety of tasks. The fact that the proteins adapt themselves to perform different tasks emerges first and foremost from a simple calculation: the human genome includes about 40,000 genes, which determine the chemical sequence and the spatial structure of the proteins. But the number of functions that proteins perform is probably much greater than this number. One of the possible explanations for this discrepancy can be based on an evolutionary process, in which the proteins are created each time anew in a different configuration, which adapts them to perform different tasks. This evolutionary process is the subject of research by Dr. Dan Toufik from the Department of Biological Chemistry at the Weizmann Institute of Science.

Dr. Toufik: "We currently know several new enzymes that were created in an evolutionary process that took place in recent years. You can think of this as a process that takes place in a molecule that is adapted to one function, but it also has a 'hobby', or 'plucking', which it is able to perform relatively rarely and to a not great degree of efficiency. But, over time, in an evolutionary process, she may develop the 'hobby' and turn it into a 'profession' or a main field of occupation."

The immune system, for example, is a microcosm in which evolution is constantly taking place. The antibodies, which are the means of "probing" and "recognition" of the system, continuously learn to recognize invaders, pollutants and new disease agents. Here, too, there is the phenomenon of a few proteins capable of performing many tasks: the number of types of antibodies is much smaller than the huge number of antigens of the foreign factors that may attack the body. Many scientists have struggled for many years with the question of how a limited variety of antibodies can recognize and neutralize an almost unlimited number of antigens. Linus Pauling stood out among these, who proposed that one antibody molecule can "adopt" a large number of structures, thus adapting itself to bind many antigens (each time to a different antigen).

When the genetic mechanism of antibody production became clear, most scientists believed that Pauling was wrong in this view. But, years later

Jefferson Pott and Cesar Milstein showed that an antibody can indeed adopt different forms. This work was supported, among other things, by the doctoral thesis of a young research student at the Feinberg Seminary of the Weizmann Institute of Science: Doron Lantz (who later became a full professor at the institute and head of the Human Genome Research Center at the institute).

Lanzet's supervisor in this work was Prof. Israel Pecht from the Weizmann Institute of Science. This doctoral thesis showed that antibodies

Those that are formed in the body are in a state of equilibrium between two different forms (at least), a kind of state of waiting. Only when the antibody encounters the antigen, it adapts itself to it. In advanced measurement techniques developed in recent years, such as the dynamic nuclear magnetic resonance measurement method developed by Prof. Lucio Friedman of the Weizmann Institute of Science (see "The Institute" number 30), protein molecules have actually been observed that change their structure as they perform their function.

In a recent study, Dr. Dan Toufik and Dr. Leo James were able to confirm the predictions of Pauling and his successors, and observe in real time structural changes that occur in a protein molecule within milliseconds. This is a process in which an antibody prepared by Prof. Zelig Ashchar from the Weizmann Institute of Science changes its shape so that it is suitable for binding different antigens. The researchers also deciphered for the first time the spatial structure of an antibody when it is bound to a different molecule each time. An antibody designed in one way binds a rather complex protein molecule. After the antibody has changed its shape, another binding site found in its recognition region binds to a specific small synthetic molecule. The findings of this study were recently published in the scientific journal SCIENCE. This whole process takes place at the outer edge of the two arms of the antibody, which is the recognition site of the antibody. This site, called FV, was discovered in the 60s by Prof. David Gavol from the Weizmann Institute of Science. Dr. Toufik says that the ability to change the structure of proteins, including antibodies, is what gives proteins "functional flexibility" and the ability to adapt more quickly. Thus, for example, the immune system is given the ability to block, using a few types of "fighters", many types of invaders, pollutants and disease agents. And on the other hand, the same ability itself is the one that can cause antibodies to attach and attack essential components of the body (which could mean the development of an autoimmune disease). This is the "horror script" as Paul Ehrlich described it. Indeed, this discovery by Dr. Toufik sheds new light on possible ways for the "horror script" to unfold and on the development of autoimmune diseases. It is possible that in the future it will help in the development of advanced ways to fight these diseases.

Two faces of the same antibody, allowing it to adapt to perform different actions. Right: the antibody binds a protein molecule (antigen); Left: It binds a small synthetic molecule
On the same subject: Response to response