Literature References | 1. KLEYN, P.W., FAN, W., KOVATS, S.G., LEE, J.L., PULIDO, J.C., WU, Y.,
BERKEMEIER, L.R., MISUMI, D.J., HOLMGREN, L., CHARLAT, O., WOOLF, E.A.,
TAYBER, O., BRODY, T., SHU, P., HAWKINS, F., KENNEDY, B., BALDINI, L.,
EBELING, C., ALPERIN, G.D., DEEDS, J., LAKEY, N.D., CULPEPPER, J., CHEN,
H., GLUECKSMANN-KUIS, M.A., CARLSON, G.A., DUYK, G.M. AND MOORE, K.J.
Identification and characterization of the mouse obesity gene tubby: a
member of a novel gene family.
CELL 85 281-290 (1996).
2. NOBEN-TRAUTH, K., NAGGERT, J.K., NORTH, M.A. AND NISHINA, P.M.
A candidate gene for the mouse mutation tubby.
NATURE 380 534-538 (1996).
3. BOGGON, T.J., SHAN, W.S., SANTAGATA, S., MYERS, S.C. AND SHAPIRO, L.
Implication of tubby proteins as transcription factors by structure- based
functional analysis.
SCIENCE 286 2119-2125 (1999).
4. NORTH, M.A., NAGGERT, J.K., YAN, Y., NOBEN-TRAUTH, K. AND NISHINA, P.M.
Molecular characterization of TUB, TULP1, and TULP2, members of the novel
tubby gene family and their possible relation to ocular diseases.
PROC.NATL.ACAD.SCI.U.S.A. 94 3128-3133 (1997).
5. NISHINA, P.M., NORTH, M.A., IKEDA, A., YAN, Y. AND NAGGERT, J.K.
Molecular characterization of a novel tubby gene family member, TULP3, in
mouse and humans.
GENOMICS 54 215-220 (1998).
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Documentation | A mutation in the mouse tub gene causes maturity-onset obesity, insulin
resistance and sensory deficits [1,2]. By contrast with the rapid juvenile-
onset weight gain seen in diabetes (db) and obese (ob) mice, obesity in
tubby mice develops gradually, and strongly resembles the late-onset obesity
observed in the human population [2]. Excessive deposition of adipose tissue
culminates in a two-fold increase of body weight. Tubby mice also suffer
retinal degeneration and neurosensory hearing loss [2]. The tripartite
character of the tubby phenotype is highly similar to human obesity
syndromes, such as Alstrom and Bardet-Biedl [2]. Although these phenotypes
indicate a vital role for tubby proteins, no biochemical function has yet
been ascribed to any family member [3], although it has been suggested that
the phenotypic features of tubby mice may be the result of cellular
apoptosis triggered by expression of the mutuated tub gene [2].
Tubby-like proteins (TULPs) are found in a wide range of multicellular
organisms [2]: for example, human TULP1 [4], which is involved in retinis
pigmentosa 14 (RP14); human TULP2 [4]; mammalian TULP3 [5]; mouse protein
p4-6, whose function is unknown; Caenorhabditis elegans hypothetical protein
F10B5.4; and a variety of other proteins from plants and Drosophila.
Mammalian tub is a hydrophilic protein of ~500 residues. The N-terminal
portion of the protein is conserved neither in length nor sequence, but the
C-terminal 250 residues are highly conserved. The C-terminal extremity
contains a cysteine residue that might play an important role in the normal
functioning of these proteins.
The crystal structure of the C-terminal core domain from mouse tubby has
been determined to 1.9A resolution [3], revealing an alpha-beta protein with
a barrel architecture. Structural analyses suggest that TULPs constitute a
unique family of bipartite transcription factors [3].
SUPERTUBBY is a 7-element fingerprint that provides a signature for the
tubby-like protein family. The fingerprint was derived from an initial
alignment of 7 sequences: the motifs were drawn from conserved regions
spanning the C-terminal half of the alignment - motif 1 spans the C-terminus
of beta strand 4 and helix 2; motif 2 encompasses strands 5 and 6 and helix
3; motif 3 spans strands 7 and 8; motif 4 spans the C-terminus of strand 9
and strands 10 and 11; motif 5 encompasses strands 12 and 13; motif 6 spans
strands 14 and 15; and motif 7, which includes the C-terminal cysteine
residue, encodes helix 6. Five iterations on SPTR39.22_17.3f were required
to reach convergence, at which point a true set comprising 22 sequences was
identified. Several partial matches were also found, all of which are tubby-
like proteins that fail to make significant matches with one or more motifs.
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