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SRBP (serum retinol binding protein)

atROH

Serum

(in vivo) and the scientist (in vitro) provide plenty of opportunities for retinol to equilibrate between CRBP(I) and potential acceptors (membranes, lipid droplets, etc.). Evidently, the large capacity of membranes and other potential acceptors does not overcome the comparatively limited capacity of CRBP(I) to sequester retinol, consistent with tight binding.

CRBP (types I and II) and CRABP (types I and II) have molecular weights of —15kDa and belong to the intracellular lipid binding protein (iLBP) gene family, which includes the various fatty acid binding proteins. The family members have similar three-dimensional structures, despite low primary amino acid conservation among nonorthologous members. These proteins form globular but flattened structures of 10 antiparallel strands of ^-sheets, 5 orthogonal to and above the other 5, referred to as a /3-clam (Figure 2). The polar head group of atROH (i.e., the functional group that undergoes esterification or dehydrogenation) lies buried deep within CRBP, protected from the milieu of oxidants, nucleophiles, and enzymes.

CRBP(I) null mice are phenotypically normal until retinol depletion, but they eliminate retinol and its esters sixfold faster than wild-type mice, presumably through enhanced catabolism via enzymes that normally have limited access. In contrast, CRBP(II) null mice pups suffer 100% mortality by 24 h after birth when born to dams fed a vitamin A-marginal diet. Retinoid binding proteins apparently confer selective advantage to vertebrates by promoted sequestering, transport, and storage of vitamin A and limiting its catabolism. CRBP(III) has been detected in mouse heart and skeletal muscle, which express little or no CRBP(I) or CRBP(II), but not in other retinoid target tissues, such as liver, kidney, and brain. CRBP(III) seems to bind about equally well with atROH, 9cROH, and 13cROH (Kd -80-110 nM). Humans express yet another CRBP, originally referred to as CRBP(III), but distinct from mouse

Figure 2 Ribbon (left) and space-filling (right) models of CRBP(I). (Courtesy of Marcia Newcomer (1995) Retinoid-binding proteins: Structural determinants important for function. FASEB Journal 9: 229-239, Louisiana State University.)

CRBP(III) and therefore really CRBP(IV). CRBP(IV) mRNA is much more abundant in human liver and intestine than CRBP(I) mRNA, but the mouse does not encode a complete CRBP(IV) gene. CRBP(IV) binds atROH with a Kd of ~60nM but does not bind cis-isomers. The precise functions of CRBP(III) and CRBP(IV) have not been clarified: Presumably, they moderate retinol metabolism, similar to CRBP(I) and CRBP(II).

CRABP(I) and -(II) do not have well-defined physiological functions. Mice doubly null in CRABP(I) and -(II) have an approximately fourfold higher rate of death from unknown causes by 6 weeks after birth than wild-type mice, but the survivors appear essentially normal, with one exception. The doubly null mouse as well as the CRABP(II)-only null mouse respectively show 83 and 45% incidence of a small outgrowth anomaly on the postaxial side of digit five, predominantly in the forelimbs. The double mutants do not exhibit enhanced sensitivity to atRA, suggesting that CRABP do not serve primarily to protect against atRA toxicity or teratogenicity.

CRALBP (~36kDa) belongs to a gene family that includes the a-tocopherol transfer protein (TTP). /« vitro, CRALBP sequesters 11cROH in the retinal pigment epithelium (RPE) of the rods, driving forward the trans to cis isomerization, and also facilitates dehydrogenation of 11cROH into 11cRCHO. Mutations in human CRALBP cause night blindness and photoreceptor degeneration.

SRBP (~20kDa) belongs to the lipocalin family, which includes apolipoprotein D, fi-lactoglobulin, odorant binding protein, and androgen-dependent secretory protein. SRBP has a globular structure formed by eight antiparallel fi-sheets in two orthogonal sheets that mold a fi-barrel. The fi-ionone ring of atROH lies deep within SRBP, whereas the hydroxyl group lies closest to the opening. atROH in serum remains bound with SRBP, despite high concentrations of a potential alternative high-capacity carrier, albumin. This illustrates the affinity of SRBP for atROH and the importance of sequestering retinoids within specific proteins. Liver is the major site of SRBP synthesis: Accordingly, liver expresses SRBP mRNA most abundantly. Extrahepatic tissues, however, also express SRBP mRNA, including adipose and kidney, but the functions of SRBP produced extrahepatically remain unknown. Knocking out the SRBP gene produces a phenotypically normal mouse, except for impaired vision after weaning. Vision can be restored after months of feeding a vitamin A-adequate diet. Thus, the eye, which consumes (but does not store) the vast majority of vitamin A, normally relies on SRBP for retinol delivery. Retinol delivered by albumin and lipopro-teins apparently supports the nonvisual functions of vitamin A, at least in the SRBP null mouse kept under laboratory conditions.

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