Dr. Dahms received her Bachelor of Science degree from Marquette University in 1980 and her Doctorate degree in Biochemistry from the Johns Hopkins University School of Medicine in 1986. She was a postdoctoral fellow at Washington University School of Medicine from 1986-1989 where she isolated and characterized the cDNA clones for the receptors involved in targeting lysosomal enzymes to the lysosome. She joined the faculty of the Medical College of Wisconsin in 1989.
PhD, Johns Hopkins University School of Medicine, 1986
BS, Marquette University, 1980
The P-type lectin family, comprised of the cation-independent mannose 6-phosphate/IGF2 receptor (CI-MPR or IGF2R) and the cation-dependent mannose 6-phosphate receptor (CD-MPR) is named for the members’ ability to recognize N-linked glycans displaying mannose 6-phosphate (M6P). These receptors play a critical role in the biogenesis of lysosomes by targeting newly synthesized acid hydrolases containing M6P to the lysosome. Furthermore, treatment of patients with lysosomal storage diseases by enzyme replacement therapy depends on cell surface CI-MPRs delivering recombinant enzymes to the lysosome. The MPRs define a larger family of proteins which contain a similar domain(s) called Mannose 6-phosphate Receptor Homology or MRH domain. These MRH domains are found in proteins in the ER and Golgi and play vital roles in protein folding and protein degradation.
The Family of MRH Proteins
Our research investigates the molecular mechanisms underlying the role of glycans and their receptors in the secretory pathway. One major focus is on the biogenesis of lysosomes and the quality control pathway of glycoprotein folding in the endoplasmic reticulum (ER).
The Role of MRH Domains in Protein Folding and Degradation
MRH domains are found in several proteins in the ER and Golgi. In collaboration Dr. Cecilia D’Alessio, we have initiated structural studies of Glucosidase II (GlcII). GlcII a heterodimic protein with a catalytic α domain and a β domain responsible for ER retention as well as housing a MRH domain essential for full GlcII activity. Through collaborations with Drs. Brian Volkman and Francis Peterson, we were able to solve the structure of this MRH domain using NMR.
The Role of MRH Domains in Lysosome Biogenesis
To begin to understand how these receptors are able to bind and release the diverse population of lysosomal acid hydrolases as they travel through the secretory pathway, we employ structural studies utilizing both X-ray crystallography in collaboration with Dr. Jung-Ja Kim as well as NMR (collaborations listed above). These studies allow us to not only investigate the protein ligand interactions through high resolution structures, but also allow us to evaluate the dynamics of the MRH domains as a function of ligand binding and pH.
Specificity of Carbohydrate Binding
CI-MPR/IGF2R is a Multifunctional Protein
Current studies are directed towards defining the signaling pathways involved in the differentiation of fibroblasts to myofibroblasts. Overabundance of myofibroblasts is associated with tissue fibrosis and corneal hazing. In collaborative studies with Dr. Sally Twining, we have shown that the CI-MPR is a critical component required for the conversion of corneal fibroblasts to myofibroblasts.
(Miller JJ, Aoki K, Mascari CA, Beltrame AK, Sokumbi O, North PE, Tiemeyer M, Kriegel AJ, Dahms NM.) FASEB J. 2019 Jan;33(1):418-429.
(Baldwin AC, Naatz A, Bohnsack RN, Bartosiak JT, Oleson BJ, Hansen PA, Dahms NM, Corbett JA.) Mol Cell Biol. 2018 04 15;38(8).
(Miller JJ, Aoki K, Moehring F, Murphy CA, O'Hara CL, Tiemeyer M, Stucky CL, Dahms NM.) JCI Insight. 2018 03 22;3(6).
(Olson LJ, Dahms NM.) Methods Mol Biol. 2018;1722:105-116.
(Olson LJ, Orsi R, Peterson FC, Parodi AJ, Kim JJ, D'Alessio C, Dahms NM.) Biochemistry. 2015 Jul 07;54(26):4097-111.
(Olson LJ, Jensen DR, Volkman BF, Kim JJ, Peterson FC, Gundry RL, Dahms NM.) Protein Expr Purif. 2015 Jul;111:91-7.
(Olson LJ, Castonguay AC, Lasanajak Y, Peterson FC, Cummings RD, Smith DF, Dahms NM.) Glycobiology. 2015 Jun;25(6):591-606.
(D'Alessio C, Dahms NM.) Curr Protein Pept Sci. 2015;16(1):31-48.
(Bohnsack RN, Warejcka DJ, Wang L, Gillespie SR, Bernstein AM, Twining SS, Dahms NM.) Invest Ophthalmol Vis Sci. 2014 Oct 30;55(12):7697-708.
(Olson LJ, Orsi R, Alculumbre SG, Peterson FC, Stigliano ID, Parodi AJ, D'Alessio C, Dahms NM.) J Biol Chem. 2013 Jun 07;288(23):16460-75.
(Maga JA, Zhou J, Kambampati R, Peng S, Wang X, Bohnsack RN, Thomm A, Golata S, Tom P, Dahms NM, Byrne BJ, LeBowitz JH.) J Biol Chem. 2013 Jan 18;288(3):1428-38.
(Castonguay AC, Lasanajak Y, Song X, Olson LJ, Cummings RD, Smith DF, Dahms NM.) Glycobiology. 2012 Jul;22(7):983-96.