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1 Structure and function of the basement membrane 连虹

2 Basement membrane (BM) Extracellular matrices (ECMs) that coat the basal aspect of epithelial and endothelial cells and surround muscle, fat, and Schwann cells

3 Basement membrane (BM) Net-like membranous structure composed by proteins and proteoglycans, separate cells from surrounding connective tissue

5 SEM of BM

6 BM Functions Transmit information Mechanical property, cell signaling Development and regeneration Embryotic mophorgenesis, andiogenesis, myogenesis Regeneration after injury Glomerular development and filtration in the kidney Component of the filtration membrane A filtration barrier between the vasculature and the urinary space Epidemal-dermal junction Stable adhesion and cell migration

7 BM components contains at least one member of the heterotrimeric laminin family one or two nidogens the heparan sulfate proteoglycans (HSPGs) perlecan and/or agrin one or more of the variants of type IV collagens Peter D. Yurchenco Cold Spring Harb Perspect Biol 2011;3:a004911

8 Laminin Heterotrimeric laminins-111 (i.e. α1β1γ1), 121, 211, 213, 221, 311, 312, 321, 332, 411,421, 422, 423, 511, 521, and 523

9 Laminin structure α 三条肽链 ( α β γ) 通过二硫键交联行成空间结构类似于一个不对称的十字架 ; β γ 十字架结构包含 3 个短臂和 1 个长臂,α β 和 γ 链各形成十字结构的一条短臂 ; 长臂由三条肽链共同构成,α 链向外延伸形成 C 端球形 G 结构域 9

10 Laminin subunit function α: cell surface adhesion and receptor interactions β&γ: mediating polymerization and nidogen-binding

11 Laminin polymerization through short arms 连蛋白网状结构的形成不同层粘连蛋白分子的短臂间互相作用形成了片层样网状结构 11

12 Cell surface anchors and receptors for laminin long arm binding Integrin: transmembrane heterodimeric receptors Hemidesmosome (HD) assembly: Laminin-332 and the a6b4 integrin Dystroglycan (DG) Receptor tyrosine kinase (RTK) Sulfatated glycolipids (SGLs)

13 BM assembly Step 1: Surface anchors and receptors on cells promote laminin trimer binding

proteins in mammals Constitute 25-35% of the whole body

14 Collagen The main structural protein of the various connective tissues in animals, the most abundant proteins in mammals Constitute 25-35% of the whole body protein content Mostly found in fibrous tissues e.g. tendon, ligaments

15 Collagen structure Many types, Most common types: I: skin, tendon, etc., over 90% in human body II: cartilage III: reticulate fiber IV: basal lamina component Collagen protein: a triple helix consists of two identical chains and another chain with slight difference

16 Collagen structure Typical repeats of Gly( 甘氨酸 )-Pro( 脯氨酸 )-X or Gly-X- Hyp (4- 羟脯氨酸 ) X: various other amino acid residues Stability relies on the hydrogen bonding of Gly and Pro/Hyp

17 Collagen IV N terminal: 7S domain C terminal: globular NC1(non-collagenous) domain

18 Collagen IV Head-to-head polymerization 通过 NC1 间头 - 头相互作用形成二聚体 ; 二聚体通过 7S 区形成八聚体 ; 八聚体进一步聚集形成 Ⅳ 型胶原网状结构

19 19

20 Ⅳ 型胶原纤维网状结构 20

21 BM assembly Step 1: Surface anchors and receptors on cells promote laminin trimer binding Step 2: Type IV collagen polymers bind with laminin polymers on the cell surface via nidogen/entactin bridging

22 nidogen/entactin( 巢蛋白 ) 22

23 Nidogen bridges 巢蛋白连接层粘连蛋白和 Ⅳ 型胶原网络 23

Sulfated Proteoglycans ( 硫酸化蛋白聚糖 ) A protein core with large glycosaminoglycan (GAG) side chains (from 1 to >100) attached to serines Some PGs contain heparan sulfate Perlecan, Agrin GAG

24 Sulfated Proteoglycans ( 硫酸化蛋白聚糖 ) A protein core with large glycosaminoglycan (GAG) side chains (from 1 to >100) attached to serines Some PGs contain heparan sulfate Perlecan, Agrin GAG chains are responsible for most of the biological properties of proteoglycans and provide charge to basement membranes Uronic acids Amino sugar GAG example: Hyaluronan ( 透明质酸 ) Heparan sulfate 硫酸乙酰肝素

25 Perlecan Provide collateral linkage to cell surface

26 BM assembly involving laminin polymerization

27 BM layers-epithelial cells Basal lamina( 基板 ) Lamina lucida ( 透明板 ) Lamina densa ( 致密板 ) Reticular lamina ( 网板 ) Basement membrane

28 TEM of BM 基板透明板致密板网板上皮细胞 Layer lamina lucida( 透明板 ) Major components Laminin, HSPG lamina densa( 致密板 ) Type IV collagen lamina reticularis( 网板 ) Reticular fiber (type III collagen)

29 The kidney's glomerular filtration barrier ( 肾小球滤过膜 ) 有孔毛细血管内皮基膜 ( 阻断大蛋白 ) 足细胞裂孔膜 ( 阻断小蛋白 ) 有孔内皮基膜裂孔膜滤过方向管腔

30 3 layers of GBM Lamina rara interna ( 内疏层 ): by the endothelial side Lamina densa ( 致密层 ):middle Lamina rara externa ( 外疏层 ): by the podocytes

31 GBM components Similar to other basement membrane Laminin (majorly LM-521), type IV collagen (majorly α3α4α5 trimers), nidogen, and heparan sulfate proteoglycan (majorly agrin)

32 Lamina rara externa Lamina densa Lamina rara interna

33 Pierson syndrome LAMB2 mutation encoding the β2 chain of laminin A combination of developmental defects that mainly affect ocular and renal function

34 Alport syndrome (hereditary nephritis) ~1/5000, the second most common inherited cause of renal failure, after polycystic kidney disease. Collagen type IV genetic mutations autosomal recessive: COL4A3 and COL4A4 mutations X-linked forms: most common, COL4A5

35 GBM anionic charge HSPG Agrin mutant mouse

37 总结 Components: laminin, type IV collagen, nidogen, HSPG (perlecan/agrin) Laminin:attach to cell surface, polymerize to form a network HSPG:collateral linkage of laminin to cell surface Nidogen: bridge of laminin and type IV collagen Type IV collagen: polymerize to form another network GBM: components similar to other BM, but with special isoforms

Microsoft PowerPoint - 1.2细菌形态结构

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