About the Institute of Structural Molecular Biology

The following commentaries are available for featured articles published by ISMB core members.
 
December 2009

Chandran V, Fronzes R, Duquerroy S, Cronin N, Navaza J and Waksman, G. Structure of the outer membrane complex of a type IV secretion system. Nature, 2009, Epub ahead of print. Doi 10.1038/nature08588 [Pubmed]

The cell walls of Gram negative bacteria consist of two membranes termed inner and outer membranes, separated by a space known as the periplasm. These bacteria have evolved at least six separate secretion systems for releasing macromolecules out of the cell into their environment. These secretion systems are large multi-protein complexes usually spanning the two membranes and the periplasmic space. Gabriel Waksman FMedSci, the director of the Institute of Structural and Molecular Biology (ISMB) and head of the departments of Structural and Molecular Biology at University College, London, and Biological Sciences at Birkbeck, has been making extensive studies of one of these secretion systems, namely the type IV secretion (T4S) system. Now a group led by Waksman, with collaborators at the Institut Pasteur and the Institut de Biologie Structurale J.P. Ebel, France, has for the first time obtained atomic resolution structural information for the outer membrane bound part of this system.

Read the full commentary for this article here.

 
April 2009

Wendler P, Shorter J, Snead D, Plisson C, Clare DK, Lindquist S, Saibil HR. Motor mechanism for protein threading through Hsp104. Mol Cell. 2009 Apr 10;34(1):81-92. [Pubmed]

Protein aggregation is generally thought to be irreversible, except in the fully denaturing conditions used by biochemists to recover unfolded proteins from inclusion bodies or other aggregates. However, the labs of Susan Lindquist in Boston and Bernd Bukau in Heidelberg discovered that in vivo aggregates resulting from severe heat stress in yeast and bacteria are redissolved by the action of a family of chaperones including Hsp104 in yeast and ClpB in bacteria, with homologues also present in plant cells. This group of Hsp100 chaperones, which form part of the diverse AAA+ superfamily of ATPases, act to remodel proteins and appear to be unique in their ability to reverse aggregation. Like other Hsp100 proteins such as the ClpA unfoldase that acts in cooperation with a protease ring, they contain an N-terminal domain followed by two tandem ATPase domains. In addition, Hsp104 and ClpB have a large, coiled coil propeller insertion which is not found in other Hsp100 proteins. The location of this coiled coil in the functional hexamer has been controversial.

Read the full commentary for this article here.


gif animation Hsp104 Movie caption of Hsp104 states in the presence of ATPγS and ATP seen as a cut away side view. The Hsp104 homology model has been fitted into one subunit to indicate the large domain movements upon ATP turnover in NBD1.
 
 
January 2009 - Two featured articles and commentaries

1- Clare DK, Bakkes P, van Heerikhuizen H, van der Vies SM and Saibil HR. A chaperonin complex with a newly folded protein encapsulated in the folding chamber. Nature, 2009, 457, 107-111 [Pubmed]

Molecular chaperones are proteins that assist other proteins to fold into their native, functional, shapes, and prevent protein aggregation. There are many types of chaperone: one chaperone family, known as the chaperonins, are barrel-shaped proteins that enclose newly formed proteins as they are released from the ribosome to fold into their native conformations, or refold proteins denatured by heat or other stresses. Electron microscopist Helen Saibil FRS from Birkbeck College, a core member of the Institute of Structural and Molecular Biology, and her group have made some of the most important structural studies of chaperonins, focusing particularly on one system, GroEL/GroES, which is found in eubacteria, mitochondria and chloroplasts.

Read the full commentary for this article here.

2- Fronzes R, Schäfer E, Wang L, Saibil HR, Orlova EV, and Waksman G. Science, 2009, 323(5911), 266-8 [Pubmed]

Gram negative bacteria have a cell wall made of two membranes separated by a thin layer of peptidoglycans. They often need to release macromolecules into their environment, a process that is known as secretion. This process is common to all living cells but is particularly complicated across this double membrane. Gram negative bacteria have, therefore, evolved a number of different types of specialist “molecular machine” for this function, six of which have so far been identified. They are believed to have evolved separately and have distinct mechanisms. Until recently, detailed structural information was available only for the type III secretion system, which is found in pathogens including Yersinia pestis, the cause of bubonic plague. Now, however, a group led by Gabriel Waksman FMedSci, the director of the Institute of Structural and Molecular Biology (ISMB) and head of the departments of Biochemistry and Molecular Biology at University College, London, and Crystallography at Birkbeck, has obtained some important information about the structure and, thus, the mechanism of the type IV secretion system .

Read the full commentary for this article here.

 
August 2008

Bagnéris C, Ageichik AV, Cronin N, Wallace B, Collins M, Boshoff C, Waksman G, Barrett T. Crystal structure of a vFlip-IKKgamma complex: insights into viral activation of the IKK signalosome. Mol Cell. 2008 Jun 6;30(5):620-31. [Pubmed]

The transcription factor NF-kappaB initiates gene expression in response to a variety of cell stimuli and is essential for animal life, although its over-expression and deregulation is closely linked to cancer development. In non-dividing cells it is “off” and associated with inhibitory proteins; it is activated by the degradation of these. The first step in initiating degradation is phosphorylation of the inhibitory proteins by a protein complex termed the IKK complex, or signalosome. Some viruses contain proteins known as vFLIPs that interact with, and activate, the signalosome, thus triggering the degradation of the inhibitory proteins, the activation of NK-kappaB, and cell division. Tracey Barrett of the School of Crystallography, Birkbeck College, London, and a core member of the Institute of Structural and Molecular Biology, and her colleagues have now solved the X-ray crystal structure of vFLIP from the Kaposi’s sarcoma herpes virus (KSHV) bound to its host target IKKgamma, shedding light on the mechanisms through which this viral protein activates the signalosome.

Read the full commentary for this article here.

 
June 2008

Remaut H, Tang C, Henderson NS, Pinkner JS, Wang T, Hultgren SJ, Thanassi DG, Waksman G & Li H. Fiber Formation across the Bacterial Outer Membrane by the Chaperone / Usher Pathway. Cell, 2008, 133, 640-52. [Pubmed]

Pathogenic bacteria that have both an outer and an inner membrane – i.e. that are Gram negative – often recognise and attach to target cells within their hosts through hair-like appendages, or pili, on their surfaces. Gabriel Waksman, head of the Institute of Structural Molecular Biology and of the Departments of Crystallography at Birkbeck and of Structural and Molecular Biology at University College London, has spent many productive years studying the structures and elucidating the mechanisms of action of these pili. Now, in a complex study combining both X-ray crystallography and electron microscopy, Han Remaut in Waksman’s group, with collaborators in Stony Brook and Washington State Universities, has solved the structure of the pilus assembly site on the bacterial outer membrane [1]. This has shed new light on the process of pilus formation.
Read the full commentary for this article here.

 
January 2008

Wendler P, Shorter J, Plisson C, Cashikar AG, Lindquist SL, & Saibil HR. Atypical AAA+ Subunit Packing Creates an Expanded Cavity for Disaggregation by the Protein-Remodeling Factor Hsp104. Cell, 2007, 131(7), 1366-77. [Pubmed]

Heat shock proteins are proteins that are over-expressed when cells are exposed to excess heat or other stresses. Functionally, they are classified as chaperones: proteins that help newly synthesized, mis-folded or aggregated proteins to re-fold. In the yeast Saccharomyces cerevisiae, the heat shock protein Hsp104 – named, like all such proteins, for its molecular weight – remodels aggregates that form after proteins are denatured by heat or chemical stress, and cooperates with another chaperone system, Hsp70/Hsp40, to re-fold the separated proteins into their native forms. Most chaperones are multi-subunit protein complexes and their structures can best be elucidated using electron microscopy. Helen Saibil FRS and her group at Birkbeck have spent many productive years studying these proteins. Now Petra Wendler, a postdoc in her group, along with collaborators at the Whitehead Institute, have determined the low-resolution structure of Hsp104 and, by fitting atomic-resolution models of its subunits into that structure, elucidated some key features of its mechanism of action.
Read the full commentary for this article here.

 
May 2007

Elad N, Farr GW, Clare DK, Orlova EV, Horwich AL & Saibil HR. Topologies of a Substrate Protein Bound to the Chaperonin GroEL. Molecular Cell, 2007, 26, 415-426 [Pubmed]

Molecular chaperones are proteins that assist other proteins to fold into their native, functional shapes, and prevent protein aggregation [2]. There are several families of chaperones, with different structures and different mechanisms. The best understood family, known as chaperonins, help fold newly synthesised proteins after they leave the ribosome, and also repair proteins that are damaged by misfolding. Helen Saibil FRS from Birkbeck College and her group have spent many productive years studying the structure of a ring-shaped bacterial chaperonin, GroEL with cryo-electron microscopy. Now, Saibil, with her Birkbeck colleague Elena Orlova and collaborators at Yale University and the Scripps Institute in the US, has shown how an unfolded form of one GroEL substrate, malate dehydrogenase (MDH), can bind to the inside surface of the chaperonin complex in several different conformations [1]. The researchers also observed that substrate binding caused changes in the conformation of the GroEL molecule itself.
Read the full commentary for this article here.

 
 
March 2007

Leiper J, Nandi M, Torondel B, Murray-Rust J, Malaki M, O’Hara B, Rossiter S, Anthony S, Madhani M, Selwood D, Smith C, Wojciak-Stothard B, Rudiger A, McDonald NQ & Vallance P. Disruption of methylarginine metabolism impairs vascular homeostasis. Nature Medicine, 2007, 13(2), 198 - 203. [Pubmed]

Nitric oxide gas (NO) is an important signalling molecule in mammals including humans. It plays a role in regulating the precise functioning of blood vessels and, therefore, in controlling blood pressure. It is synthesised by an enzyme simply known as nitric oxide synthase (NOS), which can be inhibited by methylated forms of the amino acid arginine. These inhibitors are removed from the circulation through metabolism by another enzyme, dimethylarginine dimethylaminohydrolase (DDAH). Their accumulation in blood plasma is known to be associated with increased risk of cardiovascular disease and it has been hypothesised that DDAH dysfunction may be associated with this risk. Now, Neil McDonald from Birkbeck College and Cancer Research UK, London, and a core member of the Institute for Structural Molecular Biology, working with colleagues from both institutes and from University College London, has determined the structure of the human DDAH isoform, DDAH-1, with inhibitors bound. The group also showed that reducing the activity of this enzyme, either by chemical inhibition or by gene knockout, led to accumulation of modified arginines, reduction in nitric oxide signalling, and dysfunction of the vascular system.
Read the full commentary for this article here.

 
December 2006

Okorokov AL, Sherman MB, Plisson C, Grinkevich V, Sigmundsson K, Selivanova G, Milner J, Orlova EV. The structure of p53 tumour suppressor protein reveals the basis for its functional plasticity. EMBO J. 2006, 25(21):5191-200. [Pubmed]

A protein that goes by the very unexciting sounding name of p53 plays a very important part in preventing us – most of the time – from developing cancer. This protein has been called the “guardian of the genome” [2] as it prevents potentially destructive mutations from building up in our DNA. Its mechanism of action is still poorly understood, and, until recently, attempts to discern its complete three-dimensional structure have always been unsuccessful. Now, however, Elena Orlova from Birkbeck College, London, a core member of the Institute of Structural Molecular Biology (ISMB), working with ISMB colleagues at Birkbeck and University College London, and collaborators from York, Stockholm, and Purdue University in the US, have determined the structure of the p53 molecule. This has revealed some important insights into the protein’s function. Read the full commentary for this article here.

 
October 2006

Moores CA, Perderiset M, Kappeler C, Kain S, Drummond D, Perkins SJ, Chelly J, Cross R, Houdusse A and Francis F. Distinct roles of doublecortin modulating the microtubule cytoskeleton. EMBO J. 2006, 25, 4448-4457 [Pubmed]

Click here to read the full commentary

Summary
Human brain development involves the movement of billions of immature neurons to precisely defined locations. Aberrant neuronal migration is among the most common causes of developmental neurological defects. The doublecortin family of microtubule-associated proteins are essential for neuronal migration and path-finding, with mutations in the doublecortin gene resulting in brain malformation. The microtubule cytoskeleton is essential for neuronal migration but a key question is how doublecortin regulates microtubules and contributes to accurate brain development. In a recently published paper, Carolyn Moores from Birkbeck College London, and a core member of the Institute of Structural Molecular Biology (ISMB), with fellow ISMB member Steve Perkins from University College London’s Department of Biochemistry and Molecular Biology and collaborators from the Marie Curie Research Institute, Oxted, and Paris, has now solved part of this mystery. Moores and co-workers have examined the ways doublecortin interacts with microtubules and have also shown that microtubules that are stabilised by doublecortin can act as “tracks” for the molecular motors, kinesins. These discoveries shed light on the unique function of this protein in regulating microtubule dynamics and function, and may illustrate why doublecortin mutations have such a devastating effect on brain development.

 
August 2005

Paul Rothwell, Vesselin Mitaxov, and Gabriel Waksman. Motions of the fingers subdomain of klentaq1 are fast and not rate limiting: implications for the molecular basis of fidelity in DNA polymerases. Mol Cell. 2005 Aug 5;19(3):345-55.

Whenever a cell divides, its DNA must be replicated accurately to ensure that each of its daughter cells receives an exact copy of its genome. This complex process is exceptionally precise, with the wrong base being incorporated into a growing DNA strand once in about 109-1010 cases. It is dependent on an enzyme called DNA polymerase, which selects each nucleotide and catalyses its incorporation into the new strand. Exactly how this enzyme achieves its remarkable selectivity is not yet fully understood. Gabriel Waksman from the Institute of Structural Molecular Biology (ISMB) at UCL/Birkbeck, with colleagues Paul Rothwell from ISMB and Vesselin Mitaksov from Washington University School of Medicine, have now added another piece to this puzzle. They have established that the enzyme "closes" to grip the DNA molecule very fast – much faster than the complete reaction can occur – but that this only forms a complex that is stable enough for a new nucleotide to be incorporated if that nucleotide is the correct one. This work is published in the August 2005 issue of Molecular Cell. Read the full commentary for this article here.

 
April 2005
Sarah J. Tilley, Elena V. Orlova, Robert J.C. Gilbert, Peter W. Andrew and Helen R. Saibil (2005) Structural Basis of Pore Formation by the Bacterial Toxin Pneumolysin. Cell. Volume 121, Issue 2 , 22 April 2005, Pages 247-256.

Many pathogenic species of bacteria secrete toxic proteins that can punch holes in the phospholipid membranes that surround cells, leading to leakage of the contents of the cell (cytolysis) and thus to cell death. Now, for the first time, electron microscopist Helen Saibil, her colleagues at Birkbeck College, Sarah Tilley and Elena Orlova, and collaborators Robert Gilbert from Oxford and Peter Andrew from Leicester, have shown this process in action. Read the full commentary for this article here.
 

 

 





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