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Type IV Collagens and Basement Membrane Diseases: Cell Biology and Pathogenic Mechanisms

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Type IV Collagens and Basement Membrane Diseases: Cell Biology and Pathogenic Mechanisms CHAPTER THREE Type IV Collagens and Basement Membrane Diseases: Cell Biology and Pathogenic Mechanisms Mao Mao, Marcel V. Alavi, Cassandre Labelle-Dumais and Douglas B. Gould* Departments of Ophthalmology and Anatomy, Institute for Human Genetics, UCSF School of Medicine, San Francisco, CA, USA *Corresponding author: E-mail: [email protected] Contents 1. Genomic Organization and Protein Structure of Type IV Collagens 62 1.1 Introduction and history 62 1.2 Genomic structure 64 1.3 Protein domain structure 66 1.3.1 7S domain 68 1.3.2 Triple helical domain 69 1.3.3 NC1 domain 70 2. Type IV Collagen Biosynthesis 72 2.1 Heat shock protein 47 72 2.2 Protein disulfide isomerase 73 2.3 Peptidylprolyl isomerases 74 2.4 Prolyl 4-hydroxylases 74 2.5 Prolyl 3-hydroxylases 75 2.6 Lysyl hydroxylases 76 2.7 Transport and Golgi organization 1 78 3. Type IV Collagen-Related Pathology 78 3.1 COL4A3eA6-associated pathology 78 3.1.1 Goodpasture disease 78 3.1.2 Alport syndrome 79 3.2 COL4A1/COL4A2-associated pathology 81 3.2.1 Ocular dysgenesis 81 3.2.2 Porencephaly 82 3.2.3 Small vessel disease 83 3.2.4 Cerebral cortical lamination defects 84 3.2.5 Myopathy 85 3.2.6 HANAC syndrome and nephropathy 85 4. Mechanisms for Type IV Collagen-Related Pathology 86 4.1 Overview 86 Current Topics in Membranes, Volume 76 ISSN 1063-5823 © 2015 Elsevier Inc. http://dx.doi.org/10.1016/bs.ctm.2015.09.002 All rights reserved. 61 j 62 Mao Mao et al. 4.2 Dominant negative effects of mutant proteins 87 4.3 Potential role of ER stress 88 4.4 Cell autonomous and noncell autonomous mechanisms 89 4.5 Genetic background effects suggest mechanistic heterogeneity 89 4.6 Evidence for allelic heterogeneity and mechanistic heterogeneity 90 4.7 Development of mechanism-based therapies 93 References 95 Abstract Basement membranes are highly specialized extracellular matrices. Once considered inert scaffolds, basement membranes are now viewed as dynamic and versatile en- vironments that modulate cellular behaviors to regulate tissue development, func- tion, and repair. Increasing evidence suggests that, in addition to providing structural support to neighboring cells, basement membranes serve as reservoirs of growth factors that direct and fine-tune cellular functions. Type IV collagens are a major component of all basement membranes. They evolved along with the earliest multicellular organisms and have been integrated into diverse fundamental biological processes as time and evolution shaped the animal kingdom. The roles of basement membranes in humans are as complex and diverse as their distributions and molecular composition. As a result, basement membrane defects result in multi- system disorders with ambiguous and overlapping boundaries that likely reflect the simultaneous interplay and integration of multiple cellular pathways and processes. Consequently, there will be no single treatment for basement membrane disorders, andtherapiesarelikelytobeasvariedasthephenotypes. Understanding tissue-spe- cific pathology and the underlying molecular mechanism is the present challenge; personalized medicine will rely upon understanding how a given mutation impacts diverse cellular functions. 1. GENOMIC ORGANIZATION AND PROTEIN STRUCTURE OF TYPE IV COLLAGENS 1.1 Introduction and history Basement membrane proteins are usually large and insoluble, and early structural and molecular studies were hampered by the limited availability of isolated basement membrane components. Nevertheless, elegant biochem- ical and electron microscopic studies were fundamental to the current un- derstanding of the molecular nature of type IV collagens. The discovery of type IV collagen was made by Dr Nicholas Kefalides at the University of Chicago while studying proteins extracted from glomerular basement membranes (GBMs) of dogs (Kefalides, 1966). Dr Kefalides described a Type IV Collagens and Basement Membrane Diseases 63 glycoprotein that accounted for 30% of the basement membrane by weight and whose glycine content was approximately one-third of all amino acids, suggesting that it was a type of collagen. In contrast to collagens isolated from Achilles tendon, this novel type of collagen had abnormally high levels of hydroxyproline and hydroxylysine. Type IV collagens were eventually recognized as a distinct form of collagen in that they have frequent imper- fections or interruptions in their triple helical domain and are heavily cross- linked by disulfide- and lysine-derived bonds (Kefalides, 1973). Moreover, unlike fibrillar collagens in which the amino and carboxyl termini are cleaved after being secreted into the extracellular matrix, type IV collagens exist as protomers with intact globular ends (Kefalides, 1973; Minor et al., 1976; Olsen, Alper, & Kefalides, 1973). Rotary shadowing studies revealed that type IV collagens have rod-like structures 380e390 nm in length with a terminal globular domain 8e12 nm in diameter (Timpl, Wiedemann, van Delden, Furthmayr, & Kuhn, 1981). Initially thought to be trimers made up of three identical alpha chains, biosynthetic and protease digestion ana- lyses demonstrated that distinct chains, which were later designated as a1(IV) and a2(IV), exist in a 2:1 ratio in the basement membrane (Crouch, Sage, & Bornstein, 1980; Mayne & Zettergren, 1980; Tryggvason, Robey, & Martin, 1980). Additional alpha chains were later discovered in basement membranes from other tissues (Fagg et al., 1990; Hostikka et al., 1990; Pihlajaniemi, Pohjolainen, & Myers, 1990; Zhou, Ding, Zhao, & Reeders, 1994). In mammals, six distinct but related type IV collagen alpha chains (a1(IV) to a6(IV) encoded by COL4A1 to COL4A6 genes, respectively) have been described. Based on similar exoneintron organization, exon sizes, sequence similarities, and shared features of their encoded proteins, COL4A1, COL4A3, and COL4A5 belong to the a1-like group, and COL4A2, COL4A4, and COL4A6 belong to the a2-like group (Netzer, Suzuki, Itoh, Hudson, & Khalifah, 1998). The a1(IV) chain (or COL4A1) and a2(IV) chain (or COL4A2) are considered the classical type IV collagen alpha chains, as they are present in nearly all basement membranes and have been the most extensively studied (Timpl, 1989). The other four alpha chains have more restricted distributions. For example, type IV collagen networks containing the a3(IV), a4(IV), and a5(IV) chains are present in the inner ear, testis, lung, and glomerular and tubular base- ment membranes of the kidney, whereas networks composed of the a5(IV) and a6(IV) chains are found in basement membranes of the skin, esophagus, smooth muscle cells, and synovia and in Bowman’s capsule in the kidney (Kruegel & Miosge, 2010; Mariyama, Leinonen, Mochizuki, 64 Mao Mao et al. Tryggvason, & Reeders, 1994; Ninomiya et al., 1995; Sanes, Engvall, Butkowski, & Hunter, 1990; Yoshioka et al., 1994). Moreover, in several tissues there is a developmental switch in type IV collagen network compo- sition whereby the a1(IV) and a2(IV) chains are expressed during develop- ment while other chains are acquired later during organogenesis to coexist with or replace the a1(IV) and a2(IV) network (Gunwar et al., 1998; Kalluri, Shield, Todd, Hudson, & Neilson, 1997; Kelley, Sado, & Duncan, 2002). This chapter will primarily focus on COL4A1 and COL4A2, although the general role of type IV collagens will be discussed and specific differences highlighted where appropriate. 1.2 Genomic structure Type IV collagens are major constituents of basement membranes and have been conserved since the emergence of metazoans over half a billion years ago (Boute et al., 1996; Fidler et al., 2014). The six genes exist as pairs orga- nized in a head-to-head orientation on three different chromosomes where the genes within a pair are transcribed from opposite strands (Momota et al., 1998; Poschl, Pollner, & Kuhn, 1988; Sugimoto, Oohashi, & Ninomiya, 1994). In humans, COL4A1 and COL4A2 are located on chromosome 13, COL4A3 and COL4A4 on chromosome 2, and COL4A5 and COL4A6 on the X chromosome (Figure 1). The corresponding mouse Figure 1 Chromosomal arrangements for type IV collagens and domain structures for COL4A1 and COL4A2. (A) Human (Hu) and mouse (Ms) type IV collagens are located on three distinct chromosomes as three pairs of genes transcribed from shared bidirectional promoters. (B) Type IV collagens have three functional domains. Following the signal peptide (yellow box), type IV collagens contain a 7S domain at the N-terminus, a triple helical domain and an NC1 domain at the C-terminus. Numbers above the schematics indicate amino acids in human COL4A1 or COL4A2. Gray boxes indicate repeat interrup- tions in the triple helical domain. Chr, chromosome. The program DOG v2.0 was used to draw the protein structure (Ren et al., 2009). (See color plate) Type IV Collagens and Basement Membrane Diseases 65 genes are located on chromosomes 8, 1, and X, respectively. In humans, genes encoding type IV collagens comprise 48e58 exons and span 150,000e290,000 base pairs (bp). Based upon sequence alignments, it is proposed that three independent duplication events facilitated the present genomic organization. Duplication and inversion of a single ancestral gene resulted in the formation of the first head-to-head pair that subsequently diverged. A second duplication event encompassing the entire locus created a second pair. The COL4A3/COL4A4 gene pair is more divergent from the other two gene pairs suggesting that COL4A3/COL4A4 was the product of the second duplication event. A third and final duplication later separated the more closely related COL4A1/COL4A2 and COL4A5/COL4A6 pairs (Zhou et al., 1994). This genomic head-to-head arrangement of genes that are transcribed in opposite directions is also conserved for the Col4a1 and Col4a2 orthologs (Cg25c and viking) in Drosophila (Yasothornsrikul, Davis, Cramer, Kimbrell, & Dearolf, 1997) and is distinct from the genomic orga- nization of fibrillar collagens, which are dispersed throughout the genome (Myers & Emanuel, 1987). The paired genes also share a common bidirectional promoter, which ensures the coordinated expression of type IV collagen alpha chains that will form trimeric proteins (Miner & Sanes, 1994; Peissel et al., 1995; Schmidt, Pollner, Poschl, & Kuhn, 1992; Timpl, 1989).
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