Replies

• John Hanover

  07 July 2008 | 12:42

  Nat Med. 2008 Jun;14(6):648-55. Epub 2008 May 18.
  Related Articles, Links
  
  The Ashwell receptor mitigates the lethal coagulopathy of sepsis.

  Grewal PK, Uchiyama S, Ditto D, Varki N, Le DT, Nizet V, Marth JD. The Howard Hughes Medical Institute and Department of Cellular and Molecular Medicine University of California, San Diego, La Jolla, California 92093, USA. The Ashwell receptor, the major lectin of hepatocytes, rapidly clears from blood circulation glycoproteins bearing glycan ligands that include galactose and N-acetylgalactosamine. This asialoglycoprotein receptor activity remains a key factor in the development and administration of glycoprotein pharmaceuticals, yet a biological purpose of the Ashwell receptor has remained elusive. We have identified endogenous ligands of the Ashwell receptor as glycoproteins and regulatory components in blood coagulation and thrombosis that include von Willebrand factor (vWF) and platelets. The Ashwell receptor normally modulates vWF homeostasis and is responsible for thrombocytopenia during systemic Streptococcus pneumoniae infection by eliminating platelets desialylated by the bacterium’s neuraminidase. Hemostatic adaptation by the Ashwell receptor moderates the onset and severity of disseminated intravascular coagulation during sepsis and improves the probability of host survival.

  Gil Ashwell is thrilled with the new findings and some of his thoughts are found in:

  Nature Medicine 14, 608 (2008)
  doi:10.1038/nm0608-608
  Nature Medicine 14, 606 – 608 (2008)
  doi:10.1038/nm0608-606

  Great reading and a wonderful history of the discovery and significance of the first mammalian lectin.

• Harry Schachter

  08 July 2008 | 21:14

  Hi John:
  In response to your E-mail, I just joined up. I am not sure how this thing works but it should be interesting to find out.
  I am sure that Gil would have preferred the title to read the “Ashwell-Morell Receptor” but I am equally sure that he is delighted with the paper!
  Kind regards
  Harry

• John Hanover

  08 July 2008 | 22:17

  Hi Harry,
  
  In Gil’s commentary that I referenced he definitely makes the point that it was joint effort with Anatol Morrell and mentioned that he always refers the receptor in that way. I made sure that Anatol had a copy of the paper and Jamie Marth has been communication with Gil throughout and has been wonderfully understanding.

  Thanks for joining the group and welcome!

• John Hanover

  10 July 2008 | 18:38

  Here is a paper of great interest to myself and Jerry Hart after our 25 year efforts to understand the mechanism of O-GlcNAc addition. The paper describes the first crystal structure of the O-GlcNAc transferase catalytic domain. My group had earlier solved the structure of the enzymes Tetratricopeptide domain. The paper pinpoints the site of binding to plasma membrane Phosphoinositol 3,4,5 trisphosphate. PI3K activation by signaling leads to recruitment of OGT to the cell surface. A GT-B fold characterizes catalytic domain and this enzyme and, to my knowledge, it is the first of the GT41 family members to be solved crystallographically. A Histidine (His558) is likely to be the general base facilitating the nucleophilic attack of the Ser/Thr hydroxyl group on UDP-GlcNAc.

  Brief Communication abstract

  Nature Structural & Molecular Biology 15, 764 – 765 (2008)
  Published online: 8 June 2008 | doi:10.1038/nsmb.1443

  Structure of an O-GlcNAc transferase homolog provides insight into intracellular glycosylation

  Carlos Martinez-Fleites1, Matthew S Macauley2, Yuan He1, David L Shen2, David J Vocadlo2 & Gideon J Davies

  N-Acetylglucosamine (O-GlcNAc) modification of proteins provides a mechanism for the control of diverse cellular processes through a dynamic interplay with phosphorylation. UDP-GlcNAc:polypeptidyl transferase (OGT) catalyzes O-GlcNAc addition. The structure of an intact OGT homolog and kinetic analysis of human OGT variants reveal a contiguous superhelical groove that directs substrates to the active site.