j. biol. chem.-1993-hudson-26033-6h

Minireview Vol. 268, No. 35, Issue of December 15, 26033-26036, 1993 THE JOURNAL OF B I O ~ I C A L CHEMMTRY

0 1993 by The American Society for Biochemistry and FXblecular Biology Inc. Printed in CS.A.

Type IV Collagen: Structure, Gene Organization, and Role in Human Diseases MOLECULAR BASIS OF GOODPASTURE AND ALPORT SYNDROMES AND DIFFUSE LEIOMYOMATOSIS*

Billy G. Hudson$, Stephen T. Reedersl, and Karl Tryggvasonll

From the Uepartment of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, Kansas 66160, the §Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06536-0812, and the Wiocenter and Department of Biochemistry, University of Oulu, FIN-90570 Oulu, Finland

Basement membranes (BMs)' are thin sheetlike extracellular structures that compartmentalize tissues. They provide substrata for organ cells and important signals for differentiation, mainte- nance, and remodeling of tissues. In the renal glomerulus, the BM also contributes to the molecular sieve for the selective removal of small molecules from blood. The BM is composed of several pro- teins specific for these structures such as type IV collagen (l), laminin, proteoglycan, and entactinhidogen (2). BM function is altered in a number of acquired and genetic diseases, exemplified by Goodpasture syndrome, an autoimmune disease; Alport syndrome, a progressive hereditary form of glomerulonephritis; and diffise leiomyomatosis, a hereditary disease characterized by be- nign proliferation of smooth muscle.

Recently, the molecular defects underlying Goodpasture and Al- port syndromes as well as leiomyomatosis have been linked to type IV collagen, a major structural component of BM. The major ubiquitous form of this protein is a heterotrimer containing al(IV) and a2(IV) chains (2). Studies of the molecular pathology of BM have led to the discovery of four new chains (a3 to a6) of type IV collagen that have all been'shown to be directly involved in the pathogenesis of these diseases. In Goodpasture syndrome, the a3(IV) chain is the target for the pathogenic autoantibodies (3,4). In Alport syndrome, the COL4A5 gene encoding the a5(IV) chain is mutated in the common X-chromosome-linked form of the disease (5, 61, and COL4A3 and COUA4 genes are mutated in the rare autosomal form. In leiomyomatosis, the COL4A5 and COL4A6 genes are de- leted (7 ).

Type IV collagen may now be classified as a protein family of triple helical isoforms consisting of six genetically distinct chains: the classical al(1V) and a2(IV) chains and the newly discovered a3(IV), a4(IV), a5(IV), and aG(1V) chains. The existence of the recently identified chains raises numerous unanswered questions about their biological function, structure/function relationships, gene organization and regulation, and involvement in diseases. This minireview highlights the current knowledge and recent advances in the chemistry, biology, and pathology of type IV collagen.

will be available in December, 1993. Tjle original publications of our work * This minireview will be reprinted in the Minireview Compendium, which

were supported in part by National Inetltutes of Health Grant DK-18381 and by ants from the American Heart Assoclatlon and Speas Foundatlon (to B. e"H.1, Howard Hughes Medical Institute (to S. T. R.), and Academy of Finland, The Sigrid Juselius Foundation, and Finland's Cancer Institute (to K. T.).

The abbreviations used are: BM, basement membrane; GBM, glomerular basement membrane; AS, Alport syndrome; DL, diffuse esophageal leiomyomatosis.

Structure and Supramolecular Assembly of v p e N Collagen

The building block (monomer) of the type IV collagen network in BM is a triple helical molecule composed of three a-chains (Fig. 1) (1,2). Each chain is characterized by a long collagenous domain of -1400 residues of Gly-&a-Yaa repeats, which are interrupted at several sites by short noncollagenous sequences, a -15-residue noncollagenous amino terminus, and a -230-residue noncollagenous (NC1) domain at the carboxyl terminus. Each chain is ex- tensively glycosylated, containing -50 hydroxylysine-linked disac- charide units along the collagenous domain and an asparagine- linked oligosaccharide unit located near the amino terminus (8- 10). The complete sequences of the al(1V) and a2(IV) chains of man, mouse, and Caenorhabditis elegans are known (11-16) as are those of the al(1V) chain of Drosophila (17) and sea urchin (18), a2(1V) chain of Ascaris suum (19), and the human a5W) chain (20-22). About one-third of the sequences of the human and bovine a3(IV) and a4(IV) chains and the human a6(N) chain have also been reported (7,23-29). The chains are highly homologous and fall into two classes: an al-like class composed of al(IV), a3(IV), and a5(IV) chains; and an a2-like class composed of a2(N), a4(IV), and a6(IV) chains (7,28). The existence of six a-chains allows for many different kinds (isoforms) of triple helical monomer that differ in type and stoichiometry of chains. However, little is known about their actual compositions (30). Evidence has been obtained for het- erotrimers having chain compositions of ( a l h a 2 and (&3)2a4 (2,311 and homotrimers of (c~l)~ and (a3)3 (4, 32).

The triple helical monomers self-associate forming a suprastructure (Fig. 1). Several modes of interactions are known. Monomers associate at the carboxyl termini (NC1-to-NC1) forming dimers and at the amino termini forming tetramers. The carboxyl-terminal associations are sometimes stabilized by interchain disulfide bonds between NC1 domains (33). The short noncollagenous sequence a t the amino terminus contains 4 cysteine residues that may partici- pate in both intra- and intermolecular disulfide bonds (34). In ad- dition to end-to-end interactions, triple helical domains intertwine and interact with NC1 domains forming supercoiled structures (34, 35). The flexibility required for supercoiling is presumably provided by the short noncollagenous interruptions in the triple helix. The existence of several kinds of triple helical isoforms, differing in chain composition, confers a diversity to the suprastructure in which several different combinations of monomer-monomer interactions are possible, i.e. NC1-to-NC1, amino terminus to amino terminus, helix-to-helix, and helix-to-NC1 interactions. The available evidence for NCI-NCI interactions favors association between like kinds of monomers (36).

Discriminatory molecular interactions must operate during the assembly of the suprastructure, including formation of triple helical monomers, end-to-end associations of monomers, and supercoiling. The specificity for assembly of triple helical monomers (chain selections) appears to reside within the NC1 domain of each a-chain. The NC1 domain is a highly conserved structure that has two homologous domains. The invariant residues, which include 12 cysteines in the form of six disulfide bonds, are presumed to be essential for assembly of a generic monomer, and the variable residues are presumed to govern the specificity of monomer association (28, 37). The specificity for end-to-end associations at the carboxyl terminus also appears to reside within the NC1 domain and favors association of like kinds of NC1 domains (36). The specificity for end-to-end associations at the amino terminus that govern the assembly of tetramers and supercoiling is unknown.

Tissue Distribution of a(N) Chains The six a-chains differ considerably with respect to tissue dis-

tribution. The al(1V) and a2(IV) chains appear to be ubiquitous, whereas the other chains have a restricted distribution (38). Within the kidney, the a3(IV) and a4(IV) chains have a similar distribution and are localized to the GBM (39), as is the a5(IV) chain (20), while

26033

26034 Minireview: l)pe N Collagen coL4A2- -

lagen of rend GBM. Ibp panel, electron nucrogra h shows the GBM pc- FIG. 1. Schematic illustration of the supr~tructure of type N col-

mtioned between the fenestrated capill endothekun and the foot ro- cesses ofthe epithelium ( p o d o g s ) . b f a y n e l , the building block opthe type collagen network in M is a trip e helical monomer. These self- associate forming a suprastructure in which they associate at the carboxyl termini forming dimers and at the amino termini forming tetramers. The triple helical domains intertwine and interact with the NC1 domains forming su wiled structures. Lower panel, monomers are composed of three

forming several triple helical isoforms. These are exem lified by the that are assembled fium six genetically distinct u-chaine (ul to 4 ,

(al~(q2) h f o m , (a3h(u4) +form, and a hypothetical (a5?z(&) isoform. The tnple h e l d domam 1s mkrrupted at several sites by short noncollag- enw sequences (uertkal bars), which presumably confers flexibility. The N-linked oligosaccharide CY-shaped circles) is known for the (ul)z(u2) isofcirm

EE%gia co of b. s. moue, Department of b t o m y , MeGa thetical for isoforms composed of other chams. The electron

University, Monh%anada.

the al(W and a2(IV) chains are localized to the GBM, mesangial matrix, and v a d a r and tubular BMs (39). The a5(IV) chain is also expressed in tissues other than kidney, but detailed immunohisto- chemical studies have not been reported. The a3(W and a4(W chains occur in BMs of synaptic muscle fibers but not in extraayn- aptic muscle fibers, endoneurial or perineurial nerve, or dry, whereas al(IV) and &(IV) chains occur in all these sites but in less abundance in synaptic BM (40). The a3(IV) and a4(IV) chains occur in low abundance along with al(W and a2(IV) in lens capsule BM (3) and aorta (41). The distribution of the aG(IV) chain has not been investigated at the protein level, but transcripts of the C O W 6 gene occur in a variety of tissues (7), the highest level of expression being observed in esophagus and lung. The tissue-specific diatribu-

a*%

COMA4 9 p COL4A3

I - Chromosome 13

s-:: 1 ::::: : : : wH Y ::: :: +": 9'

1 10 20 30 40 51

location of the mammalinn type N collagen gena The genes encoding FIG. 2. Schematic illustration of the organization and ctu0m-e

the six t lV collagen chains are located paim+ in a head-tu-head fashion on three%erent chromosomes. The genes deswted b horizontal bars (colored). For the C O W gene, the locataon of exom is &own by wrtical bars and introm by a horizontal line. The ex0118 are numbered from the 6' end of the gene. Intron sequences of unknown size are indicated by cireles.

toantyen fpr Goodpasturr, autoantibodies The &odpa+me autoanti- FIG. 3. Schematic illustamtion of the ols(Iv) chain PII the targe4 au-

bodies ind h e a d y to GBM of the renal glomerulus (photom ph top) Within GBM, the autoantibodies (shown in yellour) are +- to the u3(W chain. This chain is assembled into a tri e hedmole+e exemplified by the (u3)z(u4) hform. The epitop for t& autoanbbodiea MI located within the 1x3 NCl domain and is sublodized to the laat 36 amino acid residues (open circles) at the carboxyl +minus. The NC1 domaiqhss two homologous subdomains, a feature that IS common to the NC1 &nnam of + six u(IV) the. The folding of the NC1 +main, de6ned by the dx loops, 1s formed by SIX &sulfide bonds. The hght m ph of the renal glomerulus is courtesy of Dr. P. Killen, Department of P z l o g y , University of Michi- gan, Ann Arbor, MI.

tion of the newer chains presumably confers a specific BM funetion of as yet unknown nature.

!&pe N Collagen Gene8 The mammalian type IV collagen genes have a unique arrange-

ment in that they are located pairwise in a head-to-head fashion on three different chromosomes (Fig. 2) (7,4245). This implies that the genes have evolved through initial duplication and inversion of an ancestral gene followed by divergence to al- and &-like genes. The paired genes subsequently underwent two further rounds of duplication leading to the three closely opposed paire. The evolu- tion of type IV collagen genes has been Werent in lower orga- nisms, such as C. elegum, where the al(W and genes reside on Merent chromosomes (16).

The type IV collagen genes appear to be large and complex, the C O M l and C O W genes exceeding 100 kilobases containing 62

26035 Minireview: Q p e N Collagen

and 51 exons, respectively (46, 73). Comparison of COL4Al and C O W reveals considerable homology between the genes with the majority of the exons having identical sizes. Similarly, the genes for the &-like chains share high structural homology (47, 48). The C O W 1 and C O W genes, encoding the al(IV) and a2(IV) chains, share a common 130-base pair promoter region (42") that contains cis-acting elements that have uni- and bidirectional transcriptional activities (43,49). The properties of the promoters for the two other gene pairs have not been elucidated, but the distance between the transcriptional initiation sites of C O W and COW6 is 452 base pairs or less (7).

Role of 15pe IV CoZZagen in Diseases Goodpasture Syndrome-This is a lethal form of autoimmune

disease that is characterized by glomerulonephritis and pulmonary hemorrhage, which are mediated by autoantibodies that are tar- geted to glomerular and alveolar BMs. Searches for the identity of the target BM component have culminated in the discovery of the a3(IV) and a4(IV) chains (3,4,27,28) and the identification of the a3(IV) chain as the primary target autoantigen (Fig. 3) (4,361. This identity was established through extensive studies of the molecular and immunochemical properties of the soluble form of the antigen, which was obtained by collagenase digestion of alveolar, glomerular, and lens BMs (3, 4, 27, 30, 36, 5&52). The existence of the a3(IV) chain was recently verified by molecular cloning (23-261, and its identity as the Goodpasture autoantigen was verified on the basis of autoantibody binding to recombinant NC1 domains (53). Recent reports provide evidence for alternate splicing of a3(IV) mRNA, suggesting that variants of the aS(IV) chain may be expressed in certain tissues (54,551,

The epitope for Goodpasture antibodies has been localized to the carboxyl terminus of the NC1 domain of the a3(IV) chain, encom- passing the last 36 residues, as the primary interaction site (Fig. 3). The evidence for this site includes a distinctive hydrophilic amino acid sequence, the identification of lysine and cystine as critical residues, and the identi6cation of this region as critical for antibody binding using synthetic peptides (56). The epitope is seques- tered within the NC1-NC1 junction of two adjoining triple helical monomers. Upon disruption of the conformation andlor quaternary structure of this region by protein denaturants, the epitope is un- masked and becomes accessible for binding Goodpasture antibody (57). Unmasking of the epitope by infection or organic solvents, events which are thought to precede Goodpasture syndrome, may play an important role in the etiology of the disease.

Alport Syndrome (M&This is a progressive hereditary kidney disease characterized by hematuria, sensorineural hearing loss, and ocular lesions with structural defects in glomerular BM (58). The disease usually leads to terminal renal failure in males, while females are mostly less severely affected. The gene hquency has been estimated to be 15000 (58). The disease is primarily X chromosome-linked, but autosomal forms have also been reported. The X-linked form has been associated with mutations in the C O W gene encoding the a5(IV) collagen chain (5, 6, 59). More than 50 different mutations have now been identified in the C O W gene, including single base mutations, large deletions, and other major rearrangements such as inversions, insertions, and duplications (6). A striking feature is that these mutations are dispersed in the gene and no "hot spots" have thus far been identified. The COL4A5 mutations, such as those illustrated in Fig. 4, cause structural and functional defects in the type IV collagen molecule and, therefore, in the GBM network. For example, the large gene rearrangements and splice mutations could result in complete loss of the a5(IV) chain or they can cause gross stru- changes in the protein rendering it abnormally short or long. Also, glycine substitutions in the collagenous domain may inhibit the formation of the triple helix or destabilize it, analogous to the effects of corresponding mutations in type I collagen in osteogenesis imperfecta (60). The effects of the numerous amino acid substitutions in the NC1 domain may be more difficult to interpret. This highly conserved domain is probably essential for correct alignment of three u-chains prior to helix formation and for the formation of intermolecular cross-links. Any substitution of an evolutionarily conserved amino acid may, therefore, affect these functions and cause disease (61).

The extrarenal manifestations in Alport syndrome such as hear-

r1 Ran, rrprnl .I I In, Br

base mutations in the CO- gene on the u60 collagen a-% irregular thickening and splitting of GBM, .which characterizes the omer-

The aMW chain and known mutations associated with Alprt syndrome are ular lesions ofAlport syndrome, are shown rn the electron micrograpf (top).

illustrated by the horizonkrl bar (bottom). The black mgwm represent the noncollagenous interruptions of the triple helix. The electron micro aph is courte of D. W. Richardson, De artment of Pathology, University of%ansaa MedicsCenter, Kansas City, K.8.

FIG. 4. Schematic illu&mtion of the consBQuBpcB8 of known

ing loss and ocular lesions can v a r ~ ~ both with respect to presence and severity even within the same kindred. The reason for this is unclear, and at this time the phenotype generated by a given mutation cannot be predicted. An interesting feature is that some a5(IV) mutations are associated with the failure of stable incorpo- ration and even absence of the a3(IV) and a4(IV) chains into Alport GBM (62-64). At present, the mechanism linking a mutation in a5(IV) chain with failure to incorporate the a3(IV) and a4(IV) chains is unknown. Mutations in a5(IV) chain may result in defective molecular assembly with subsequent proteolysis of the a3(IV) and a4(IV) chains or may result in defective synthesis through some unknown effects on transcription or translation.

Autosomal inherited forms of Alport syndrome have been reported, although they are much more rare than the X-linked forms. These cases also develop hematuria, end-stage renal failure, and disrupted GBM structure. f ieb inary studies indicated recessive mutations in both COL4A3 and COW4 genes.2

Diffuse Esophageal Lewmyomatosis (Dw"This is a rare disease characterized by beNgn smooth muscle cell proliferation that af- fects the esophagus as well as the female genital tract and tracheo- bronchial tree (65). This disease has also been associated with Alport syndrome (65). In fact, 28 cases from 14 families, which have been documented, show cosegregation of DL and Alport syndrome (66). Deletion of the 5' end of the COL4A5 gene has been reported in three children with AS-DL (661, and deletions involving the 5' end of COL4A5 extending into the second intron of the adjacent COW6 gene were recently described in four patients with the disease (7). Mutations involving only C O W or COL4A6 have, as yet, not been found in the disease. It is quite possible that, in some cases, the a5(IV) and a6(IV) chains are not present in the same triple helical molecule. This is supported by the observation of a different lack of expression of the two genes in different tissues such as esophagus and kidneys (7).

Conclusions and Perspectives It is now well established that type IV collagen comprises a

family of triple helical isoforms consisting of at least six genetically distinct chains having a tissue-specific distribution. With the ex- ception of the triple helical isoform comprised of the al(IV) and a2(IV) chains, little is known about the chain composition of isoforms comprised of the other chains, or their suprastructure. Also, their tissue-specific functions, other than structural ones, are com-

S. T. Reeders, unpublished data.

26036 Minireview: Tj pletely unknown. However, recent studies leading to the discovery of the minor a3(IV), a4(IV), a5(IV), and aG(IV) chains and demon- stration of their involvement in the pathogenesis of Goodpasture and Alport syndromes and leiomyomatosis have provided new in- sight into the structure and properties of specialized BMs. The gene mutations underlying Alport syndrome and leiomyomatosis, to- gether with the limited tissue distribution of the corresponding chains, clearly indicate specific biological functions for these chains, including a vital role in the molecular sieve function of GBM and in cell differentiation such as that of smooth muscle.

The recent advances in the chemistry, biology, and pathology of type IV collagen have had and will undoubtedly continue to have a significant clinical impact. The stage is now set to delineate the role of the six u(IV) collagen chains in diabetic renal disease and tumor metastasis, as type IV collagen has been implicated in the pathogenesis of both (67-72). Knowledge of the pathogenic mechanism underlying Goodpasture syndrome now provides the basis for development of new diagnostic tests and therapeutic procedures. Ex- act diagnosis of Alport syndrome and hereditary leiomyomatosis is now possible, and the ground is even ready for the development of somatic gene therapy.

of the original publications on ty e IV collagen. We are deeply indebted to our AcknowledgmentsSpace limitations preclude the acknowledgment of all

graduate students, postdoctoraf fellows, technicians, and collaborators for their contributions to the work summarized here. We thank Bill Paige for his excellent artwork.

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