Similarly to laminins, the three collagen IV isoforms can aggregate into networks that also can be heterotypic

Similarly to laminins, the three collagen IV isoforms can aggregate into networks that also can be heterotypic. laminins with 5-chains. The core protein of perlecan was an exclusive component of this network whereas its heparan sulfate chains were integrated into the collagen IV-containing network. Nidogens 1 and 2 occurred in both networks but did not form strong molecular cross-bridges. Their incorporation into one network appeared to be masked after their incorporation into the other one. We conclude that this epidermal basement membrane is usually a composite of two structurally impartial networks that are tightly connected in a spot-welding-like manner by perlecan-containing aggregates. basement membrane-like patches interspersed into the papillary dermis (3). Information is usually mediated in both directions of the dermal-epidermal junction zone and results in appropriately fine-tuned functions of the epidermis and the dermis. The structure and assembly mechanisms of basement membranes in general have been subject to intensive investigation by morphological, developmental, genetic, and biochemical approaches (for recent reviews, see Refs. 4, 5). Basement membranes are supramolecular composites of two impartial, but physically connected networks whose quantitatively major components are laminins and isoforms of collagen IV, respectively. Laminins constitute a family of heterotrimeric Phenoxodiol proteins with three distinct polypeptide chains, called -, -, and -chains, forming cross-shaped molecules (6). The long arm arises by an -helical supercoil of the C-terminal portion of all three chains. The N-terminal portions of each polypeptide form the Phenoxodiol three short arms. Each polypeptide of the short arms folds into a string of several globular domains, LE- and LN-domains, which are essential for the supramolecular assembly. The C-terminal portion of the -chain folds into five globular LG-domains which, in some cases, are truncated to three globules by proteolytic processing. The LG-domains are mainly involved in cellular interactions via integrins. In the epidermal basement membrane, laminins can self-assemble into networks, but the mode of integration of laminin 332 remains unknown because this laminin lacks most of the short arms after proteolytic processing. Collagen IV is usually another major component of basement membranes. There are six genetically distinct -chains of collagen IV, called 1(IV) through 6(IV), but only three distinct heterotrimers occur in tissues, Phenoxodiol (1(IV))22(IV), 3(IV) 4(IV) 5(IV), and (5(IV))26(IV). Similarly to laminins, the three collagen IV isoforms can aggregate into networks that also can be heterotypic. However, in the epidermal basement membrane, only (1(IV))22(IV)- and (5(IV))26(IV)-heterotrimers can be found (7). The aggregation of suprastructural laminin networks is usually orchestrated by clusters of cell surface (macro)molecules, such as integrins, dystroglycan, or sulfatides, that bind and, thereby, concentrate laminins at the plasma membrane. They also reduce the activation energy of self-assembly by juxtaposing interacting surfaces of the nascent suprastructures at the nanoscale. Furthermore, selective binding in each case of discrete mixtures of macromolecular components ascertains the formation of networks with appropriate tissue-specific functions. Finally, the laminin- and collagen IV-containing networks are linked to each other to form functional basement membranes. In an attempt to identify the molecular linkers, studies of direct interactions between individual basement membrane macromolecules have been performed. The results have hinted at an important role in this context of nidogens 1 and/or 2 (for reviews, see Refs. 5, 8). Mouse models have shown that the presence of certain laminin chains is required already at very early development, before implantation of the embryos into the uterine wall. Genetic ablation of other chains causes early postnatal lethality or PGF still milder phenotypes (for review, see Ref. 6). The inactivation of the and genes encoding collagen IV also is incompatible with life, although only at later stages of gestation. In view of the network adaptor role assigned to the nidogens, the knock-out of the nidogen genes had surprisingly moderate consequences in mice. Phenoxodiol The single knock-outs were viable and fertile, and even the compound ablation of both nidogen genes did not cause immediate postnatal lethality. It was concluded from the studies that, despite the severe developmental abnormalities observed in the double knock-outs, nidogens were not essential for basement.