Activating drug discovery for Gaucher disease

Summaries of newsworthy papers published online in Nature and the Nature Research Journals on 24 December 2006. Including: New genetic cause of an immunodeficiency syndrome found and New streptococcal virulence factors.

NATURE AND THE NATURE RESEARCH JOURNALS PRESS RELEASE

For papers that will be published online on 24 December 2006

This press release is copyrighted to the Nature journals mentioned below.

This press release contains:

* Summaries of newsworthy papers:
Activating drug discovery for Gaucher disease - Nature Chemical Biology
New genetic cause of an immunodeficiency syndrome found - Nature Genetics
New streptococcal virulence factors - Nature Structural and Molecular Biology

* Mention of papers to be published at the same time with the same embargo
* Geographical listing of authors

PDFs of all the papers mentioned on this release can be found in the relevant journal’s section of http://press.nature.com. Press contacts for the Nature journals are listed at the end of this release.

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PLEASE CITE THE SPECIFIC NATURE JOURNAL AND WEBSITE AS THE SOURCE OF THE FOLLOWING ITEMS. IF PUBLISHING ONLINE, PLEASE CARRY A HYPERLINK TO THE APPROPRIATE JOURNAL’S WEBSITE.

*************** NATURE CHEMICAL BIOLOGY ******************

(http://www.nature.com/nchembio <http://www.nature.com/natureneuroscience>)

[1] Activating drug discovery for Gaucher disease

DOI: 10.1038/nchembio850

Scientists have identified a new structural form of the protein that is mutated in Gaucher disease, providing important information on how the disease may be treated, according to a paper to be published in the February issue of Nature Chemical Biology.

Gaucher disease arises from the inability of cells to hydrolyze a particular lipid, leading to liver dysfunction among other serious problems. One emerging treatment for this disease is enzyme enhancement therapy, in which helper small molecules assist a disabled protein in performing its normal function. The success in identifying the appropriate helper molecules, however, depends on knowing what the enzyme looks like.

Petsko and colleagues have discovered that the enzyme acid-beta-glucosidase, mutations of which directly cause Gaucher disease, can exist in two different states. The ‘inactive’ structure had already been seen, but was not useful in designing new treatments. The authors now report the ‘active’ structure of the enzyme, which is needed for cells to function normally. Gaucher disease is a serious disorder that needs improved treatments. By knowing what the active form of the enzyme looks like, scientists will be able to design molecules that help this protein more effectively.

Author contact:
Gregory A. Petsko (Brandeis University, Waltham, MA, USA)
Tel: +1 781 736 4903; E-mail: [email protected] <mailto:[email protected]>

******************* NATURE GENETICS ***********************

(<http://www.nature.com/naturegenetics>)

[2] New genetic cause of an immunodeficiency syndrome found
DOI: 10.1038/ng1940

A gene called HAX1 is mutated in some individuals with an immunodeficiency syndrome known as severe congenital neutropenia (SCN), according to a study to be published in the January issue of Nature Genetics. The identification of mutations in HAX1 ends a 50-year search for the genetic basis of one form of this disease.

SCN comprises a group of disorders characterized by low levels of neutrophils in peripheral blood and bone marrow. As neutrophils are part of the body’s defense against bacteria, affected individuals can develop life-threatening infections without treatment. The recessive form of SCN is also called Kostmann disease, after its discoverer, who identified it in 1956.

Christoph Klein and colleagues have now identified mutations in HAX1 in three Kurdish families and 19 other unrelated individuals with recessive SCN. The HAX1 protein is found in mitochondria, the energy-producing compartments of the cell, and the authors show that it is required to maintain viable neutrophils. Although recessive SCN is rare, the authors suggest that individuals with this or other forms of SCN may have mutations in other genes that normally promote the survival of neutrophils.

Author contact:
Christoph Klein (Hannover Medical School, Germany)
Tel: +49 511 532 6718; E-mail: [email protected] <mailto:[email protected]>

Other papers from Nature Genetics to be published online at the same time and with the same embargo:

[3] The gene encoding adipose triglyceride lipase (PNPLA2) is mutated in neutral lipid storage disease with myopathy
DOI: 10.1038/ng1951

*******NATURE STRUCTURAL AND MOLECULAR BIOLOGY*********

(<http://www.nature.com/natstructmolbiol>)

[4] New streptococcal virulence factors
DOI: 10.1038/nsmb1187

Degradation of host glycogen is an important factor in bacterial pathogenesis, according to the authors of a study in the January issue of Nature Structural and Molecular Biology. Alisdair Boraston and colleagues report structure-function studies of surface anchored carbohydrate binding modules - CBMs - from Streptococcus pneumoniae.

Humans are constantly exposed to microbes. The relationships can be mutually beneficial (symbiotic), to the benefit of one partner without necessarily harming the other (commensal) or to the benefit of one partner at the expense of the other (pathogenic). Some of the factors that drive a particular host-microbial relationship in one direction or another are the kind of carbohydrates, including glycogens, expressed by the host.

S. pneumoniae is an invasive pathogen that penetrates lung cells and goes deeper into the tissue by passing from cell to cell without killing all of the cells in its path. The authors used x-ray crystallography to study the mechanism by which pathogenic streptococci target the lungs. They found that tandem CBMs from a streptococcal enzyme may act to specifically target intracellular lung glycogen, leading to its degradation. These findings may suggest potential new therapeutic strategies that target the disruption of glycogen interaction and/or degradation as a way to treat streptococcal lung infections.

Author contact:
Alisdair Boraston (University of Victoria, British Columbia, Canada)
Tel: +1 250 472 4168; E-mail: [email protected] <mailto:[email protected]>

Other papers from Nature Structural & Molecular Biology to be published online at the same time and with the same embargo:

[5] SUMOylation of TR2 orphan receptor involves Pml and fine-tunes Oct4 expression in stem cells
DOI: 10.1038/nsmb1185

[6] An arginine ladder in OprP mediates phosphate-specific transfer across the outer membrane
DOI: 10.1038/nsmb1189

***************************************************************

Items from other Nature journals to be published online at the same time and with the same embargo:

Nature (<http://www.nature.com/nature>)

[7] Interleukin-22, a TH17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis
DOI: 10.1038/nature05505

[8] The nuclear receptor LXR is a glucose sensor
DOI: 10.1038/nature05449

[9] Sonic hedgehog function in chondrichthyan fins and the evolution of appendage patterning
DOI: 10.1038/nature05436

[10] The APOBEC-2 crystal structure and functional implications for the deaminase AID
DOI: 10.1038/nature05492

[11] The twisted ion-permeation pathway of a resting voltage-sensing domain
DOI: 10.1038/nature05396

[12] Structure prediction for the down state of a potassium channel voltage sensor
DOI: 10.1038/nature05494

Nature PHYSICS (http://www.nature.com/naturephysics <http://www.nature.com/naturematerials>)

[13] Phase separation and suppression of critical dynamics at quantum phase transitions of MnSi and (Sr1−xCax)RuO3
DOI: 10.1038/nphys488

[14] Classes of complex networks defined by role-to-role connectivity profiles
DOI: 10.1038/nphys489

[15] Local fluctuations in the ageing of a simple structural glass
DOI: 10.1038/nphys482

NATURE MATERIALS (<http://www.nature.com/naturematerials>)

[16] Negative normal stress in semiflexible biopolymer gels
DOI: 10.1038/nmat1810

Nature MEDICINE (<http://www.nature.com/naturemedicine>)

[17] Artificially engineered magnetic nanoparticles for ultra-sensitive molecular imaging
DOI: 10.1038/nm1467

[18] Polyvalent vaccines for optimal coverage of potential T-cell epitopes in global HIV-1 variants
DOI: 10.1038/nm1461

[19] Calreticulin exposure dictates the immunogenicity of cancer cell death
DOI: 10.1038/nm1523

Nature NEUROSCIENCE (<http://www.nature.com/natureneuroscience>)

[20] Separate neural substrates for skill learning and performance in the ventral and dorsal striatum
DOI: 10.1038/nn1817

[21] Structural basis for modulation of Kv4 K+ channels by auxiliary KChIP subunits
DOI: 10.1038/nn1822

Nature BIOTECHNOLOGY (http://www.nature.com/naturebiotechnolgy)

[22] F0 generation mice fully derived from gene-targeted embryonic stem cells allowing immediate phenotypic analysis
DOI: 10.1038/nbt1263

[23] Absolute protein expression profiling estimates the relative contributions of transcriptional and translational regulation
DOI: 10.1038/nbt1270

Nature IMMUNOLOGY (<http://www.nature.com/natureimmunology>)

[24] Antigen-receptor genes of the agnathan lamprey are assembled by a process involving copy choice
DOI: 10.1038/ni1419

[25] Scaffold protein Dlgh1 coordinates alternative p38 kinase activation, directing T cell receptor signals toward NFAT but not NF-kappaB transcription factors
DOI: 10.1038/ni1422

[26] The adaptor protein CARD9 is required for innate immune responses to intracellular pathogens
DOI: 10.1038/ni1426

NATURE CELL BIOLOGY (<http://www.nature.com/naturecellbiology>)

[27] Retinoblastoma protein and anaphase-promoting complex physically interact and functionally cooperate during cell-cycle exit
DOI: 10.1038/ncb1532

[28] Abnormal bundling and accumulation of F-actin mediates tau-induced neuronal degeneration in vivo
DOI: 10.1038/ncb1528

[29] Gata-3 is an essential regulator of mammary-gland morphogenesis and luminal-cell differentiation
DOI: 10.1038/ncb1530

[30] Myosin VI targeting to clathrin-coated structures and dimerization is mediated by binding to Disabled-2 and PtdIns(4,5)P2

DOI: 10.1038/ncb1531

[31] Loss of centrosome integrity induces p38-p53-p21-dependent G1/S arrest
DOI: 10.1038/ncb1529

NATURE METHODS (<http://www.nature.com/nmeth>)

[32] An Escherichia coli expression-based method for heme substitution
DOI: 10.1038/nmeth984

******************************************************************

GEOGRAPHICAL LISTING OF AUTHORS

The following list of places refers to the whereabouts of authors on the papers numbered in this release. The listing may be for an author's main affiliation, or for a place where they are working temporarily. Please see the PDF of the paper for full details.

ARGENTINA
San Carlos de Bariloche: 13

AUSTRALIA
Parkville: 29

BRAZIL
Rio de Janeiro: 13

CANADA:
Hamilton: 13
London: 27
Toronto: 13
Vancouver: 6
Victoria: 4

CHINA
Beijing: 21

FRANCE
Evry: 3
Nantes: 3
Paris: 3, 19
Toulouse: 3
Villejuif: 19

GERMANY
Freiburg: 2
Garching: 13, 16
Hannover: 2

IRAN
Tehran: 2

ITALY
Rome: 18

JAPAN
Chiba: 13
Kyoto: 13
Tokyo: 24

KOREA
Seoul: 17

NETHERLANDS
Amsterdam: 16, 29
Nijmegen: 3
Rotterdam: 29

SPAIN
Barcelona: 11

SWEDEN
Stockholm: 2
Uppsala: 2

UNITED KINGDOM
Cambridge: 22, 30
London: 2

UNITED STATES OF AMERICA
Alabama
Birmingham: 18
California
Berkeley: 11, 32
La Jolla: 8
Los Angeles: 10, 25
Palo Alto: 23
San Diego: 8
San Francisco: 7, 12
Colorado
Boulder: 20
Illinois
Chicago: 9
Evanston: 14
Normal: 24
Kentucky
Lexington: 13
Maryland
Baltimore: 9
Bethesda: 2, 25
Frederick: 31
Massachusetts
Boston: 1, 11, 18, 26, 27, 28
Cambridge: 1
Charlestown: 18, 27, 28
Waltham: 1
Worcester: 31
Michigan
Ann Arbor: 29
Minnesota
Minneapolis: 5
New Jersey
Cranbury: 1
New Mexico
Los Alamos: 18
Santa Fe: 18
New York
Albany: 31
Ithaca: 21
New York: 13
Tarrytown: 22
Throggs Neck: 13
North Carolina
Durham: 18
Ohio
Athens: 15
Pennsylvania
Philadelphia: 16
Pittsburgh: 12
Texas
Austin: 23
Dallas: 12
Houston: 26

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For media inquiries relating to embargo policy for all the Nature Research Journals:

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Nature Cell Biology (London)
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Nature Chemical Biology (Boston)
Andrea Garvey
Tel: +1 617 475 9241, E-mail: [email protected]

Nature Genetics (New York)
Orli Bahcall
Tel: +1 212 726 9311; E-mail: [email protected] <mailto:[email protected]>

Nature Immunology (New York)
Laurie Dempsey
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Nature Materials (London)
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Nature Medicine (New York)
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Michelle Montoya
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Published: 24 Dec 2006

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