The distribution and function of alternatively spliced insertions in hDlg.
hDlg is the human homolog of the Drosophila Discs-large tumor suppressor. As a member of the MAGUK (membrane-associated guanylate kinase) family of scaffolding proteins, hDlg is composed of three PDZ (PSD-95, Dlg, and ZO-1) repeats, an SH3 (Src homology 3) motif, and a GUK (guanylate kinase-like) domain. Additionally, hDlg contains two regions of alternative splicing. Here we identify a novel insertion, I1B, located N-terminal to the PDZ repeats. We further analyze the tissue-specific combinations of insertions and correlate those results with the distribution of protein isoforms. We also identify the functions of the two alternatively spliced regions. The N-terminal alternatively spliced region is capable of binding several SH3 domains and also moderates the level of protein oligomerization. Insertions in the second region are responsible for determining the localization of hDlg, with insertion I3 targeting the protein to the membrane regions of cell-cell contact and insertion I2 targeting the protein to the nucleus.
McLaughlin
Margaret
M
Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
Hale
Robert
R
Ellston
Dawna
D
Gaudet
Suzanne
S
Lue
Robert A
RA
Viel
Alain
A
D048868:Adaptor Proteins, Signal Transducing; D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D000074288:Discs Large Homolog 1 Protein; D004330:Drosophila; D016147:Genes, Tumor Suppressor; D051528:Guanylate Kinases; D006801:Humans; D008565:Membrane Proteins; D008969:Molecular Sequence Data; D016254:Mutagenesis, Insertional; D009703:Nucleoside-Phosphate Kinase / Q000737:chemistry; D017433:Protein Structure, Secondary; D011506:Proteins / Q000737:chemistry / Q000235:genetics*; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D018909:src Homology Domains
D048868:Adaptor Proteins, Signal Transducing; C513314:DLG1 protein, human; D000074288:Discs Large Homolog 1 Protein; D008565:Membrane Proteins; D011506:Proteins; D009703:Nucleoside-Phosphate Kinase; D051528:Guanylate Kinases