Richard N. Sifers, Ph.D.
Baylor College of Medicine
Ph.D., University of Oklahoma Heath Sciences Center, Oklahoma City
Postdoctoral, Baylor College of Medicine, Houston
2008: Recipient of an 8-Stranded Beta-Barrel Jelly Roll award for “Best Lecturer” in the core curriculum of the BCM Graduate School of Biomedical Sciences
2008:Recipient of a Fulbright & Jaworski L. L. P. Faculty Excellence Award (in the category of Teaching and Evaluation), BCM
2009:Inducted as member, Academy of Distinguished Educators, BCM
2009:Recipient of an 8-Stranded Beta-Barrel Jelly Roll award for “Best Lecturer” in the core curriculum of the BCM Graduate School of Biomedical Sciences
2009:Invited Keynote Lecturer, 3rd Protein Misfolding and Neurological Disorders Meeting, Port Douglas, Queensland, Australia
2010:Recipient of the Barbara and Corbin J. Robertson, Jr. Presidential Award for Excellence in Education, BCM
2010:Inducted as member, BCM Society of Presidential Educators
Deployment to the cell surface provides a mechanism by which proteins can play pivotal roles in cell-to-cell contact, signal transduction, embryonic development and tissue morphogenesis. Assembly of these newly synthesized polypeptides into distinct biologically-active conformations is facilitated by transient physical interactions with molecular chaperones. Secretory and membrane-associated proteins undergo conformational maturation following translocation of the newly synthesized polypeptides into the endoplasmic reticulum (ER). Quality control machinery within the ER monitors protein structure during folding such that only correctly folded molecules are deployed to distal sites. Importantly, hindered intracellular transport and accompanying disposal of mutant gene products contribute to the pathogenesis of cystic fibrosis, hypercholesterolemia, and osteogenesis imperfecta. Lung and liver diseases result from heritable alpha1-antitrypsin deficiency.
Based on our molecular and biochemical analysis of the latter disorder a picture has emerged in which the processing of asparagine-linked oligosaccharides targets the misfolded molecule for degradation by the proteasome. Degradation is preceded by specific oligosaccharide processing events which lead to "molecular capture" by the lectin calnexin prior to degradation. These findings reveal that an extensive overlap exists between protein folding and quality control machinery, and demonstrate how the combinatorial actions of a distinct set of processing enzymes and unique family of lectins can recognize, select, and sort misfolded glycoproteins for intracellular disposal. Thus, asparagine-linked oligosaccharide processing and recognition represent the meeting point between glycoprotein folding and disposal processes. Our future goals are to identify the evolutionary development of quality control mechanisms, and elucidate their contribution to disease pathogenesis and cell-fate determination.
- Sifers RN. Resurrecting the protein fold for disease intervention. Chem Biol, 20(3):298-300 (2013). PubMed
- Pan S, Cheng X and Sifers RN. Golgi-situated endoplasmic reticulum α-1, 2-mannosidase contributes to the retrieval of ERAD substrates through a direct interaction with y-COP. Mol Biol Cell, 24(8):1111-21 (2013). PubMed
- Fong JJ, Nguyen BL, Bridger R, Medrano EE, Wells L, Pan S and Sifers R. ß-N-Acetyglucosamine (O-GIcNAc) is a novel regulator of mitosis-specific phosphorylations on histone H3. J Biol Chem, 287(15):12195-203 (2012). PubMed
- Pan S, Wang S, Utama B, Huang L, Blok N, Estes MK, Moremen KW and Sifers RN. Golgi localization of ERManl defines spatial separation of the mammalian glycoprotein quality control system. Mol Biol Cell, 22(16):2810-22 (2011). PubMed
- Pan S, Iannotti MJ and Sifers RN. Analysis of serpin secretion, misfolding, and surveillance in the endoplasmic reticulum. Methods Enzymol, 499:1-16 (2011). PubMed
- Sifers RN. Intracellular processing of alpha1-antitrypsin. Proc Am Thorac Soc, 7(6):376-80 (2010). PubMed
- Sifers RN. Medicine. Clearing conformational disease. Science, 329(5988):154-5 (2010). PubMed
For more publications, see listing on PubMed.
Department: Pathology and Molecular & Cellular Biology
Address: Baylor College of Medicine
One Baylor Plaza
Houston, TX 77030
Additional Links: Pathology