all biochemistry stories

Comprehensive model first to map protein folding at atomic level

Thu, 12 Jul 2007 09:53:08 -0400

Scientists at Harvard University have developed a computer model that, for the first time, can fully map and predict how small proteins fold into three-dimensional, biologically active shapes. The work could help researchers better understand the abnormal protein aggregation underlying some devastating diseases, as well as how natural proteins evolved and how proteins recognize correct biochemical partners within living cells.

The technique, which can track protein folding for some 10 microseconds - about as long as some proteins take to assume their biologically stable configuration, and at least a thousand times longer than previous methods - is described this week in the Proceedings of the National Academy of Sciences (PNAS).

Snaring secrets of the Venus flytrap

70652986 — Mon, 26 Mar 2007 05:36:21 -0400

While "speed" is not a word most people associate with the plant kingdom, the Venus flytrap closes its v-shaped leaves in just one-tenth of a second - fast enough to accomplish a feat thousands if not millions of backyard barbecuers fail at each summer: snaring a fly. So how can a plant pull this off? By storing and releasing elastic energy, according to Gordon McKay Professor of Applied Mathematics and Mechanics Lakshminarayanan Mahadevan. Mahadevan likened the Venus flytrap's hinged leaves to a plastic lid that is bowed in one direction and then suddenly pops the other way. While waiting for prey, the plant's leaves are bowed outward, opening the hinged trap. When an insect touches the hairy triggers located inside of the trap, the plant moves water in the leaves, changing their curvature and suddenly snapping them closed. "It is a relatively simple mechanism, but the plant is actively controlling it," Mahadevan said. The plant then excretes digestive enzymes that break down the meal, providing nutrients that the plant cannot get from the poor, boggy soil where it grows naturally. The research, published in the Jan. 27, 2005 issue of the journal Nature, was conducted largely while Mahadevan was at the University of Cambridge before coming to Harvard in 2003.

Disparate proteins structurally identical

70652986 — Mon, 26 Mar 2007 05:36:40 -0400

Gerhard Wagner, the Elkan Blout professor of biological chemistry and molecular pharmacology, and Tucker Collins, the S. Burt Wolbach professor of pathology at Harvard Medical School and Children's Hospital, made a crucial connection between two unrelated proteins. They were studying a particular type of protein when a database search for proteins with similar structures turned up a fragment of the HIV-1 capsid protein. Given the propensity for retroviral proteins to rapidly mutate, this conserved interface offers an attractive therapeutic target for two reasons. It may be less likely to mutate, and it may be essential for capsid dimerization, which, in turn, is essential for viral replication.

RNA-making apparatus seen to uncoil and recoil DNA

70652986 — Mon, 26 Mar 2007 06:24:08 -0400

Eukaryotic cells like to keep their DNA under wraps, winding the long strands of nucleic acid around millions of little protein complexes. This bead-on-a-string structure, called chromatin, ensures that the DNA is protected and also helps to condense the long strands of nucleic acid so they more easily are accommodated in the nucleus.

Chromatin also makes life slightly more complex, however, because it must be unwound when specific genes are to be transcribed into RNA for protein synthesis then rewound when the gene is shut off. Though considerable advances have been made unraveling the mysteries of chromatin disassembly, figuring out how the reassembly occurs has been more challenging. But recent work from Harvard Medical School Professors Kevin Struhl, the David Wesley Gaiser professor of biological chemistry and molecular pharmacology, and Stephen Buratowski, professor of biological chemistry and molecular pharmacology, reveals that the process requires the cooperation of the transcription machinery itself. In the Nov. 18, 2005 Cell and the Dec. 22, 2005 Molecular Cell, Buratowski and Struhl, respectively, show that restoration of the chromatin structure depends on the chemical modification of core histones, the proteins that make up the chromatin bead. When acetyl groups are added to histone proteins they lose some affinity for DNA. This is partly why chromatin falls apart in the first place. But what Struhl, Buratowski, and colleagues show is that deacetylation, which helps to restore chromatin, depends on proteins associated with RNA polymerase II, the enzyme that transcribes DNA into RNA.

The work suggests that just as the transcription machinery promotes unwinding of chromatin as it travels along the DNA making RNA, it also helps to protect the DNA by repackaging the unraveled chromatin it leaves in its wake. The findings lend support to the theory, proposed independently by Struhl and HMS professor of genetics Fred Winston, that restoring the chromatin structure is essential, particularly because it eliminates a potentially disastrous scenario the initiation of DNA transcription in the wrong place, which could lead to cell death.

Matrix-buster inhibitor has second way to throttle angiogenesis

70652986 — Mon, 26 Mar 2007 05:32:47 -0400

Matrix metalloproteinases (MMPs) and their regulators, the tissue inhibitors of metalloproteinases (TIMPs), form an intriguing partnership. MMPs work by breaking down the dense matrix surrounding cells, freeing them to wander the body during processes like metastasis and angiogenesis. TIMPs rein in the MMPs, essentially cutting off the supply of migrating cancer or endothelial cells. Given the TIMPs' anti-angiogenic action, it is no wonder that pharmaceutical companies have been rushing to develop synthetic MMP-inhibiting agents. Yet in clinical trials, these manmade versions have often performed poorly, producing serious side-effects while failing to stop angiogenesis in cancer patients. It now appears that inhibiting the MMPs is not enough to arrest the new blood vessel growth that accompanies tumors. Working in a mouse model, Marsha Moses, Cecilia Fernandez, and their colleagues found that TIMP-2, a variant known to stifle angiogenesis in vivo, owes its power to stop cancer-related angiogenesis to its unique ability to inhibit endothelial cells from proliferating, rather than its ability to bind MMP. What is more, TIMP-2's anti-proliferative power appears to be restricted to a small, easily synthesized region of the molecule, Loop 6. " "It is a new angiogenesis inhibitor, it is small, and it is bioavailable," said Moses, Harvard Medical School associate professor of surgery at Children's Hospital. The study appears in the Oct. 17, 2003 Journal of Biological Chemistry.

Researchers make new compounds from protein

70652986 — Mon, 26 Mar 2007 05:30:21 -0400

Over the years, scientists have repeatedly sought to use a cell's protein-making process to create new drugs and other compounds. They have had some dramatic successes, such as inducing bacteria to produce human insulin by splicing human insulin-producing genes into the bacteria's DNA. They have been limited, however, to creating only natural substances like insulin by nature's insistence that anything a cell makes is drawn from the 20 naturally occurring amino acids. Harvard Medical School researchers Stephen Blacklow and Anthony Forster's findings have now changed - in a test tube anyway - a fundamental law of biology termed the "central dogma." The central dogma says that information flows in a rigid way within a cell, originating in the DNA, moving to the RNA, which then couples with a ribosome to create proteins out of the naturally occurring amino acids according to the universal genetic code. Blacklow and Forster figured out a way around the system's natural constraints by essentially hijacking the DNA's messages in transit. They did this by switching the chemical adaptors that respond to the DNA's instructions. Instead of delivering the natural amino acids that the DNA calls for, these new adaptors introduce their custom-made unnatural amino acids.

New multiple sclerosis drugs are found

70652986 — Mon, 26 Mar 2007 05:23:08 -0400

Five years ago, scientists at Harvard University began to take a close look at Copolymer 1, a treatment for multiple sclerosis, that is put together from a string of amino acids, or protein pieces, assembled in random order. "We wanted to determine if there are one or two active compounds within the random Copolymer 1 mixture that we could isolate and use to produce a more effective drug," says Jack L. Strominger, Higgins Professor of Biochemistry, who leads the effort. "That turned out not to be the case." However, chemical juggling of the protein pieces led to four novel copolymers that are more potent than Copolymer 1. Two of them look especially promising, and Strominger's team injected them into mice with a nervous system disease similar to human MS.

Remote-control immunity up close

70652986 — Mon, 26 Mar 2007 05:17:52 -0400

When we receive a wound, disease-fighting cells rush to the scene to do combat with bodily invaders. But how does this work? When we receive a wound, cells near the wound send out chemical signals to attract disease-fighting cells. These chemical messengers travel to the lymph nodes in our bodies. The lymph node is, according to Ulrich von Andrian, Harvard Medical School associate professor of pathology at the Center for Blood Research, "the staging area for our fight against infection in the periphery." The whole system operates, according to von Andrian, by "remote control." The research contributes to our understanding of how the immune system works in the body. Von Andrian and his colleagues published their work in the November 2001 issue of the Journal of Experimental Medicine.

Protein may play double role in issuing genetic gag order

70652986 — Mon, 26 Mar 2007 05:12:17 -0400

So cells can differentiate and maintain their specialized identities, large sections of unneeded genes must be turned off. During cell division, the stability of every chromosome depends upon sections of chromosomes remaining silent. Cancer is believed to be due, in part, to the loss of cell identity and unstable chromosomes. Aging also may be linked to silencing activities. Only recently have the detailed biochemical mechanisms behind this process of turning genes on and off started to come to light. That is thanks to the work of several labs on the best defined model system, the budding yeast, and Sir2, a repressor protein that is required for all known examples of yeast silencing.