Pazza, I would recommend you check out some of the other 4 player build threads to get a lot of good ideas, advice, and lessons learned that will help you decide what's the best solution for YOU. Everyone has opinions and will offer thoughts, but remember its ultimately your build and what makes you happy and fits your needs.
If you think your 4 player cabinet is worth having even if you only play with 4 people twice a year, then go for it. But the point is, think about the games you enjoy and realistic number of players that will use it on average to decide if it's worth it for you. You definitely could make player 3 and 4 be modular additions or use game pads for rare occasional play.
As far as number of buttons, again very game dependent and how future proof you want it. I would go with 4 to cover everything out there so far. If you anticipate bringing on new PC games from steam (ie they have a new Ninja Turtles coming out) then you might regret only having 2 buttons on the outer players later on. Hard to say but most 4 player games tend to use between 2 and 4 buttons.
As far as size, there are ways to help get it around. For example, the 4 player build I'm currently doing uses threaded inserts so it can be completely disassembled and reassembled to fit through any area needed. You could theoretically have any size you want that way as long as it fits in your final resting place and you don't mind assembly. Sure beats trying to lug around a 300+ lb monster. Regarding the screen orientation, if you're mostly sticking to classics, I agree with Mike that a vertical orientation solution is a pretty cool trick to keep the over all screen size closer to the correct aspect ratios for the games, but still have a decent sized screen. I almost went that route and am hoping I don't regret my choice later. One plus to using a wide screen is you can have digital bezel graphics displayed if desired. Vertical may help make the 4 player design slightly thinner on the main cab but only from the cab perspective. You still need proper spacing of the players which will make your CP big no matter what. If your players are all crammed up and hitting each other as they interact with the controls, you probably won't have many enjoyable 4 player sessions.