The tubby-like proteins, a family with roles in neuronal development and function

Abstract

The identification of a mutation at the tubby (Tub) locus, which causes obesity and neurosensory degeneration, led to the discovery of the tubby-like proteins (TULPs). Tub and the genes that encode three tubby-like proteins (TULP1- TULP3) form a novel, small gene family that plays an important role in maintenance and function of neuronal cells during development and post-differentiation. Although exploration of the molecular function of these genes is still in its infancy, recent biochemical studies have provided ‘entry points’ into pathways whose elucidation will further our understanding of TULP action. In addition, mRNA expression and translocation of the TUB protein have been shown to be regulated by thyroid hormone and by G-protein-coupled receptor signaling, respectively. These latter findings may help to link the cellular function of TUB to known mechanisms for energy homeostasis.

MicroRNA and MicroRNA-Target Variants Associated with Autism Spectrum Disorder and Related Disorders

“…TUB (TUB Bipartite Transcription Factor) and SCP2 have been studied in individuals with neuronal disorders [ 35 , 36 ]. TUB is part of the Tubby signaling pathways that are important during neurodevelopment [ 37 ]. A TUB frameshift mutation in three siblings was associated with retinal dystrophy and obesity [ 36 ].…”

A novel homozygous Tub mutation associated with autosomal recessive retinitis pigmentosa in a consanguineous Chinese family

“…Thus far, five mammalian tubby-like proteins ( TULPs) family members (TUB, TULP1, 2, 3 and 4) have been identified with an important role in the maintenance of the central nervous system [15]. The TULPs are characterized by a unique "tubby domain" of ~260 amino acid residues in the C-terminal [31], which forms a central hydrophobic α-helix transversing the β-barrel structure [9].…”

“…The 'tubby domain' contains a phosphatidylinositol-binding region specifically binding to phosphatidylinositol 4,5-bisphosphate (PIP2) [8] and a DNA-binding domain (DBD) that selectively binding to double-stranded DNA [9]. Although the N-terminal motifs of the TULPs are poorly conserved [32], the C-terminal "tubby domains" of the TULPs are remarkedly conserved with 55-95% identity across species from plants to humans [15], implying an evolutionarily conserved function [9]. Structure-function analysis by Sunshin Kim et al [24] demonstrated that the tubby domain in Tub plays a crucial role in its subcellular localization and its solubility.…”

“…Tub (MIM #601197), also known as retinal degeneration 5 (rd5), maps to 11p15.4 and codes for the tubby-bipartite transcription regulator [8,9]. TUB, abundantly expressed in the retina, brain, and cochlea [10][11][12] with dual localization to the plasma membrane and nucleus [8], has been implicated in energy balance [13,14], retinal degeneration [10], and neuronal regulation in mice [15]. The underlying molecular mechanism, however, remains to be fully elucidated.…”

Computational analyses reveal a prognostic impact of TULP3 as a transcriptional master regulator in pancreatic ductal adenocarcinoma

“…(C) In the MEXP2780 sample data, patients who had low TULP3 expression levels exhibited a 3.4 times greater chance of survival compared to those who had high expression levels and a difference between the two expression groups of p-value = 0.00496. plays an essential role during mammalian development, since mutations in TULP3 exhibit embryonic lethality with defects during neural tube closure. [30][31][32] The tubby domain is positively charged at the carboxy-terminal region and possesses a nuclear localization conserved sequence, which enables its role as a transcription factor. This region of the TULP3 protein binds to the plasma membrane, specifically to phosphatidylinositol-4,5bisphosphate (PIP 2 ), a phospholipid highly enriched in the membrane.…”