Dimers, Tetramers, and DNA – Oh my.

REFERENCE:  Aramayo et al. Nucleic Acids Research (2011) 
                        Epub ahead of print: July 14^th, 2011

The tumor suppressor p53 transactivates genes involved in cell cycle arrest, apoptosis or senescence.  Several key papers have established p53’s structure as a dimer of dimers.  The central core domain, where the majority of cancerous mutations reside, is responsible for sequence specific binding to DNA.  Despite years of structural work, several questions, including the spatial arrangement of all p53’s domains and the basis for dominant negative p53 mutant effects, remain.  A recent paper by Aramayo et al. discusses a 21 Å cryo electron microscopy structure where full length murine p53 is bound to DNA duplexes bearing consecutive p53 recognition elements (REs).  Their data suggests that only one core domain of each dimer binds to an RE while the other two core domains remain unoccupied.  This type of complex requires a ~ 45° rotation of one dimer relative to the other upon DNA binding, a movement which is notable in other DNA binding proteins.  This rotation also allows for the C terminal domains, known to bind DNA nonspecifically, to come in contact with the duplex, while the N terminal domains become poised for interaction with the replication machinery.  It was previously established that p53 dimers are formed co-translationally while tetramers are formed post-translationally.  One allele bearing a core domain mutation will lead to dimers where each subunit bears the mutation.  This information, along with the described structure, offers a mechanistic explanation for why one mutated allele leads to dominant negative effects in p53 function: with one mutated allele, 75% of the p53 tetramers will be unable to bind DNA.

Double Duty Inhiitor?

REFERENCE: Hansen et al. Structure (2011) 19, pgs 919 – 929.

Malaria, a disease that causes 1 million deaths per year, is caused by a Plasmodium parasite.  Cysteine proteases (CPs) expressed by the parasite are implicated in key process of both parasitic life stages: liver and blood.  Interestingly, host cell CPs are also integral to infection.  Given the destructive nature of proteases, CPs of both host cells and parasites must be regulated site-specifically and temporarily.  In the July issue of Structure, Hilgenfeld and colleagues discuss the structure of the Plasmodium cysteine protease falcipain-2 (FP-2) in complex with the C terminus of their identified CP inhibitor from Plasmodium berghei (PblCP-C).  PblCP-C has an Ig-like ß sandwich fold and its closest structural relative is identified as chagasin, an I42 inhibitor family member.  Loops L0, L2, L4, and L6 protrude from PblCP-C (shown) into the active site of FP-2, thus occluding substrate binding.  The authors compare the PblCP-C:FP-2 structure to other solved inhibitor complexes and conclude that the major interactions responsible for inhibition are conserved between the structurally unrelated inhibitors, but the PblCP-C L0 interactions with FP-2 are unique to this complex.  Intriguingly, the structure of L0 also explains why PblCP-C is a potent inhibitor of the papain-like protease cathepsin L but not cathepsin B.  Because PblCP is necessary for host cell invasion, it is postulated that this CP inhibitor could block potentially deleterious protease activity at crucial moments, such as host-cell invasion, or inhibit host cell CPs (such as the cathepsin-like caspases).  It also provides a framework for developing small molecule inhibitors of the critically important FP-2.

Welcome!

Welcome to my new spin off blog!

My original intention for the blog Amedeo was to explain science topics to those who don’t have a strong scientific background.  I’m proud to say that blog is booming and readership is growing.  I truly enjoy writing those weekly posts and it makes me so happy to hear “I understand what you’re talking about!”  Science isn’t a mystery – I swear.

However, other readers out there have stronger scientific background and, like me, probably don’t have a tremendous amount of time to read the newest literature.  In between running experiments, dealing with everyday life, or being buried with work, the latest breakthroughs on vaccines or recent models for protein function are simply overlooked.

As a member of AAAS (The American Association for the Advancement of Science), the journal Science is emailed to me each week.  I usually only spend a few moments reading the headlines before moving on to other emails or other interests.  I know I’m not alone in that behavior and I very much want to change it!  This blog will now allow me to practice writing short reviews of interesting science papers as well as give my readers an idea of what is currently being published.  

I will be posting in weekly installments with new posts appearing on Saturdays or Sundays, the same as with Amedeo.  However, I’ll amend how I post based on how things are going.  Stay tuned as I learn to juggle two blogs!  And, as always, check back for new updates, layouts, or pictures as I tend to work on the blogs most days even if a new post hasn’t appeared.  They are constantly being updated!