The TRPV ion channels mediate responses to many sensory stimuli including heat, low pH, neuropeptides, and chemical ligands. All TRPV subfamily members contain an intracellular N-terminal ankyrin repeat domain (ARD), a prevalent protein interaction motif. The 1.6-Å crystal structure of the TRPV2-ARD, with six ankyrin repeats, reveals several atypical structural features. Repeats one through three display unusually long and flexible fingers with a large number of exposed aromatic residues, whereas repeats five and six have unusually long outer helices. Furthermore, a large counterclockwise twist observed in the stacking of repeats four and five breaks the regularity of the domain, altering the shape of surfaces available for interactions with proteins or other cellular ligands. Both solution studies and crystal packing interactions indicate that the TRPV2-ARD does not form homo-oligomers, suggesting that the ARD of TRPV ion channels may be used for interactions with regulatory factors rather than in promoting tetrameric assembly of the ion channels. The transient receptor potential (TRP)3 channels are a large family of cation channels that are important in processes ranging from sensory signaling to magnesium homeostasis (1). TRP channels, like many voltage-and ligand-gated channels, have six membrane-spanning segments and are thought to function as tetramers. TRP channels also have large N-and C-terminal cytosolic regions containing putative protein interaction and regulatory motifs. The TRP channel family is divided into six subfamilies based on sequence identity and function, including the TRPV subfamily (named after the vanilloid receptor, TRPV1); there is little homology in the N-and C-terminal cytosolic regions between subfamilies.The six mammalian TRPV channels are important in sensory and pain perception and in calcium homeostasis. At the molecular level, TRPV1 and TRPV2 are both activated at noxious temperatures (Ͼ43°C and Ͼ52°C, respectively) (2, 3). TRPV1 is also gated by exogenous ligands such as capsaicin and resiniferatoxin (reviewed in Ref. 4). TRPV3 is activated by warm temperatures (Ͼ32-39°C) and camphor (5-7), whereas TRPV4 senses osmotic stimuli, heat (Ͼ27°C), and phorbol esters (8 -10). The more distant TRPV homologs TRPV5 and TRPV6 are regulated by intracellular Ca 2ϩ levels and mediate transepithelial Ca 2ϩ transport in the kidney and intestine (11). The N-terminal region of TRPV channels contains ankyrin repeats, which are likely to be essential for channel function as their deletion in TRPV1 impairs activation (12). Furthermore, the TRPV5 and TRPV6 ankyrin repeats were implicated in the tetrameric assembly of the channels (13,14). Ankyrin repeats are 33-residue sequence motifs often involved in protein-protein interactions and present in many eukaryotic and prokaryotic proteins with functions that include signaling, cytoskeleton integrity, transcription, and cellular localization (15,16).Determining the three-dimensional structures of TRPV channel domains is an important step in understand...
Common variable immunodeficiency (CVID) refers to a group of disorders where differentiation and maturation of B cells into plasma cells are affected, leading to decreased or defective immunoglobulin production and subsequent immunodeficiency. Symptoms may present at any age between 5 and 72 years, although more severe forms often manifest earlier in life. Milder forms may not be detected. We present an intriguing case of a 69-year-old man presenting with recurrent pneumonia caused by a rare organism , eventually determined to be caused by CVID. The patient had a good clinical outcome after receiving immunoglobulin replacement therapy.
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