Can a “chemical rope” help treat ALS?

In this week’s issue of PNAS, Brandeis postdoc Jared Auclair and Chemistry grad student Kristin Boggio, together with Professors Greg Petsko, Dagmar Ringe, and Jeffrey Agar discuss Strategies for stabilizing superoxide dismutase (SOD1), the protein destabilized in the most common form of familial amyotrophic lateral sclerosis. Working from the hypothesis that the mechanism of the toxicity involves dimer destabilization and dissociation as an early step in SOD1 aggregation, they looked for mechanisms to stabilize SOD1 using chemical cross-linking. Cross-linking the dimer using 2 adjacent cysteine residues results in substantial stabilization of relevant SOD1 mutants.

A "Chemical rope" stabilizes SOD1 protein. Mutations that destabilize SOD1 in motor neurons are associated with familial ALS

Read more about Prof. Agar, this research, and its potential for this technique in the treatment of ALS at Brandeis NOW

For ClC transporters, breaking up is hard to do

Many ion channels and transporters exist as oligomers with each subunit containing a distinct transport pathway.  A classic example is the ClC family of chloride channels and transporters that are homodimeric with a pathway for chloride permeation or chloride/proton anti-port through each subunit.  Because of their dimer structure, they have come to be known as “double-barreled shotguns” for chloride movement across the membrane.

Since each subunit appears to possess the complete machinery required for transport, it is  often wondered whether ClCs need to be dimeric in order to carry out function.  In a study published last week in Nature, Brandeis researchers Janice Robertson, Ludmila Kolmakova-Partensky and Professor Christopher Miller answer this question.  By introducing two tryptophan mutations at the dimer interface, they designed a variant of a ClC transporter that could be purified and crystallized as an isolated monomer.  With this, they were able to determine that the monomer alone was fully capable of carrying out chloride and proton transport function.  These results show that the dimer is not required and that the monomer is the fundamental unit of transport in ClCs.  The question of why ClCs evolved as dimers remains a key question for understanding membrane protein structure.

From sequence to consequence: Petsko-Ringe lab celebration

From Sequence to Consequence: Celebrating 30 Years of Science with
Dagmar Ringe and Greg Petsko

June 18-19, 2010
8:30 a.m. – 5:00 p.m.
Shapiro Auditorium

On September 4, 1980, Drs. Dagmar Ringe and Greg Petsko entered into an official collaboration, and the scientific community has never been the same since.  Now, 30 years later, their joint lab at Brandeis University is putting together a symposium to celebrate their combined lifetimes of achievement.  This 2-day event features 20 speakers who either trained or collaborated with the lab, plus a dinner reception on Friday night.  Registration is now open to all members of the Brandeis community.  Details and registration can be found at http://www.bio.brandeis.edu/PRSymposium2010/.  The registration code is scc30.

Dagmar and Greg

Structural diversity of amyloid fibrils

Amyloid fibrils are associated with Alzheimer’s disease. In a recent study published in J. Mol. Biol., Nikolaus Grigorieff and coworkers used electron cyro-microscopy to study these structures and show that these fibrils coexisting in solution can be extremely polymorphic.

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